4-1801844-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000142.5(FGFR3):c.749C>G(p.Pro250Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,606,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:43O:2

Conservation

PhyloP100: 5.85

Variant links:

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

FGFR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 4-1801844-C-G is Pathogenic according to our data. Variant chr4-1801844-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1801844-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5 link	c.749C>G	p.Pro250Arg	missense_variant	Exon 7 of 18	ENST00000440486.8	NP_000133.1	P22607-1Q0IJ44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 link	c.749C>G	p.Pro250Arg	missense_variant	Exon 7 of 18	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

238970

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1454808

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722916

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:43Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Muenke syndrome

Pathogenic:19

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 26, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM6 strong, PP3 supporting -

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 28, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474), is suspected to be due to variants with a loss of function, and dominant negative mechanism, respectively (PMID: 25614871, PMID: 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMID: 26740388, PMID: 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMID: 26740388, PMID: 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (2 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is very well established as pathogenic, and has been reported in many individuals with Muenke syndrome with variable expressivity. Additionally, it has been observed less commonly in individuals with Saethre-Chotzen or craniosynostosis syndrome, and can be inherited from an asymptomatic parent (ClinVar, PMID: 26740388). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 20, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS1, PS3, PM2 -

Feb 04, 2022

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Muenke syndrome (MIM #602849) is diagnosed based on the presence of the recurrent p.Pro250Arg variant (PMID: 8841188). -

Dec 11, 2019

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG evidence PS3, PP2, PP3 -

May 06, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PP3, PP5 -

Feb 28, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a well-established cause of Muenke syndrome (PMID: 9042914, 26740388, 20301628). Functional characterization demonstrates that this missense change enhances ligand-binding in vitro compared to wild-type and affects endochondral ossification (PMID: 14613973, 22016144). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.001% (2/267,378) and is thus presumed to be rare. It is a non-conservative amino acid substitution and is predicted by multiple in silico tools to be deleterious to protein function. Based on the combined evidence, the c.749C>G (p.Pro250Arg) variant is classified as pathogenic. -

Feb 22, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FGFR3 c.749C>G variant is a single nucleotide change in the FGFR3 gene that changes the amino acid proline at position 250 in the protein to arginine. This variant has been previously reported in several unrelated patients with Muenke syndrome (PMID: 9042914, 26740388, 20301628) (PS4_moderate). Functional characterization demonstrates that this missense change enhances ligand-binding in vitro compared to wild-type and affects endochondral ossification (PMID: 14613973, 22016144) (PS3). The variant was detected de novo in a patient with no family history of the disease (PS2). This variant has been reported in dbSNP (rs4647924) and is rare in population databases (2/270,300 in gnomAD, 0 homozygotes) (PM2). It is a non-conservative amino acid substitution and is predicted by multiple in silico tools to be deleterious to protein function (PP3). -

not provided

Pathogenic:10

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFR3: PS2:Very Strong, PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3 -

Sep 27, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 250 of the FGFR3 protein (p.Pro250Arg). This variant is present in population databases (rs4647924, gnomAD 0.003%). This missense change has been observed in individual(s) with Muenke syndrome, but has also been identified in individuals with features of Saethre-Chotzen syndrome or other craniosynostosis syndromes (PMID: 9042914, 10094188, 10861678, 15915095, 26740388). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16340). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FGFR3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 14613973). For these reasons, this variant has been classified as Pathogenic. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 20, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple individuals with features overlapping other craniosynostosis syndromes, including Pfeiffer syndrome, Crouzon syndrome, and Saethre-Chotzen syndrome (Bellus et al., 1996; Muenke et al., 1997; Mulliken et al., 1999; Kruszka et al., 2016); however, some of the clinical features of individuals with the above syndromes may be rare in patients with this variant (Muenke et al., 1997); Reported in some individuals with radiographic abnormalities of hands and feet but without craniosynostosis, having normal head size or macrocephaly (Muenke et al., 1997; Kruszka et al., 2016a); Published functional studies demonstrate a damaging effect including disruption of endochondral and perichondrial ossification of the cranial base in mice (Laurita et al., 2011; Yasuda et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11746040, 22622662, 24127277, 28551036, 31837199, 14613973, 26740388, 11424131, 12884424, 23325524, 19449410, 21204234, 22016144, 24705944, 15915095, 21233754, 21403567, 22446440, 23851839, 20592905, 24168007, 11197897, 24728327, 12087222, 20707699, 11428324, 8841188, 10541159, 27683237, 27568649, 26028288, 9279764, 9600744, 17103449, 17036334, 31111620, 31130284, 9042914, 20301588, 32238909, 31564432, 31019026, 32369273, 32382396, 9107244, 18000976, 32510873, 33502061) -

Achondroplasia

Pathogenic:3

Jul 31, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The p.R250R pathogenic variant is the most common pathogenic variant found in MNKS patients with variable expressivity [PMID 9107244, 9279764] -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FGFR3 c.749C>G (p.Pro250Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238970 control chromosomes. c.749C>G has been reported in the literature in multiple individuals affected with Muenke syndrome (example, Paumard-Hernandez_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhancement in ligand binding in vitro (Ibrahimi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14613973, 25271085). ClinVar contains an entry for this variant (Variation ID: 16340). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypochondroplasia

Pathogenic:2

Aug 04, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016340 /PMID: 8841188 /3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Pro250Leu, p.Pro250Thr) have been reported to be associated with FGFR3-related disorder (PMID: 12362036, 31721094). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FGFR3-related disorder

Pathogenic:2

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGFR3 c.749C>G variant is predicted to result in the amino acid substitution p.Pro250Arg. This variant has been documented as one of the most common variants associated with syndromic craniosynostosis, and in particular with autosomal dominant Muenke syndrome (Muenke et al. 1997. PubMed ID: 9042914; Mulliken et al. 1999. PubMed ID: 10541159; Roscioli et al. 2013. PubMed ID: 24127277; Kruszka et al. 2016. PubMed ID: 26740388). Of note, this variant has been reported in one patient without craniosynostosis but with hearing loss and developmental delay (Patient 15, Table 1, Kruszka et al. 2016. PubMed ID: 26740388). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Mar 26, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_Very Strong, PS3, PM1, PM5_Supporting -

FGFR3-related chondrodysplasia

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 21, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.749C>G (p.P250R) alteration is located in exon 7 (coding exon 6) of the FGFR3 gene. This alteration results from a C to G substitution at nucleotide position 749, causing the proline (P) at amino acid position 250 to be replaced by an arginine (R)._x000D_ _x000D_ Based on the available evidence, the FGFR3 c.749C>G (p.P250R) alteration is classified as pathogenic for Muenke syndrome. Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/270300) total alleles studied. The highest observed frequency was 0.003% (1/34950) of Latino alleles. The FGFR3 c.749C>G (p.P250R) alteration is a well-established disease-causing alteration of Muenke syndrome and the only reported pathogenic mutation in patients with Muenke syndrome (Bellus, 1996; Kruszka, 2016). This amino acid position is well conserved in available vertebrate species. Functional analysis of mouse models of Muenke syndrome harboring the mouse equivalent of the p.P250R alteration (p.P244R in mice) show that the alteration disrupts endochondral and perichondrial ossification in the cranial base (Laurita, 2011) as well as the temporomandibular joint development by reducing hedgehog signaling and endochondral ossification (Laurita, 2011; Yasuda, 2012). Surface plasmon resonance analysis and X-ray crystallography demonstrated enhanced binding of the mutant structure compared to wildtype (Ibrahimi, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Crouzon syndrome;C0036572:Seizure;C0266294:Unilateral renal agenesis;C1306710:Facial asymmetry;C1856266:Coronal craniosynostosis;C3806604:Infantile axial hypotonia;C4316903:Generalized non-motor (absence) seizure

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer;C5774286:Lacrimoauriculodentodigital syndrome 2

Pathogenic:1

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Craniosynostosis syndrome

Pathogenic:1

Apr 30, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Saethre-Chotzen syndrome

Pathogenic:1

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Achondroplasia;C0410529:Hypochondroplasia;C1864436:Muenke syndrome;C1868678:Thanatophoric dysplasia type 1;C2677099:Crouzon syndrome-acanthosis nigricans syndrome

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 02-18-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;T;.;.;T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T;T;T;T;.;T

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

L;.;L;L;.;L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.0

D;D;D;D;.;D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;D;D;.;D;D

Sift4G

Benign

0.23

T;T;T;T;D;T;D

Polyphen

1.0

D;D;B;D;.;D;.

Vest4

0.73

MutPred

0.89

Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);.;

MVP

0.96

MPC

0.35

ClinPred

0.75

GERP RS

3.1

Varity_R

0.95

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over