rs397507529

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_002834.5(PTPN11):c.844A>G(p.Ile282Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,600,326 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I282M) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:31

Conservation

PhyloP100: 8.95

Variant links:

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) in NM_002834.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112473033-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

PP5

Variant 12-112473031-A-G is Pathogenic according to our data. Variant chr12-112473031-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112473031-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.844A>G	p.Ile282Val	missense_variant	Exon 7 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.844A>G	p.Ile282Val	missense_variant	Exon 7 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.844A>G	p.Ile282Val	missense_variant	Exon 7 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1448136

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721280

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:11

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.844A>G(p.Ile282Val) in PTPN11 gene has been reported has been reported previously in heterozygous state in individuals affected with disease name (Swarts JW et. al., 2022). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S, et al., 2008). This variant is present in a mutational hotspot. A different missense variant p.Ile282Met has been reported at the same position as Pathogenic/Likely pathogenic in the ClinVar Database (Atik T, et al., 2016).This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Isoleucine at position 282 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen - Possible damaging/Benign, SIFT - Damaging, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ile282Val in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as pathogenic. -

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 08, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2021

Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 17, 2023

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: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated protein-tyrosine phosphatase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with Noonan syndrome and LEOPARD syndrome (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4_MOD,PM1,PM5,PM2_SUP,PP3 -

not provided

Pathogenic:10

Sep 09, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM1, PM2, PP2 -

Jan 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.844A>G; p.Ile282Val variant (rs397507529) is reported in the literature in several individuals affected with noonan syndrome including multiple de novo occurrences (Binder 2005, Inoue 2020, Jongmans 2011, Pierpont 2009, Tartaglia 2001, Tartaglia 2003, Yang 2018). This variant occurs within the highly conserved phosphotyrosine phosphatase (PTP) domain and in vitro/in vivo functional analyses demonstrate a significant increase in basal level phosphatase activity consistent with the gain-of-function disease mechanisms of noonan syndrome (Fragale 2004, Martinelli 2008, Tartaglia 2006). This variant is also reported in ClinVar (Variation ID: 40525). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 282 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.525). Based on available information, this variant is considered to be pathogenic. References: Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. PMID: 15985475. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat. 2004 Mar;23(3):267-77. PMID: 14974085. Inoue T et al. Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients. Clin Epigenetics. 2020 Jun 16;12(1):86. PMID: 32546215. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260. Martinelli S et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet. 2008 Jul 1;17(13):2018-29. PMID: 18372317. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. PMID: 19077116. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759. Tartaglia M et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID: 12717436. Yang L et al. Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel. BMC Med Genet. 2018 Dec 12;19(1):212. PMID: 30541462. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies show that I282V exhibits a gain-of-function effect on the protein (Fragale et al., 2004; Martinelli et al., 2008); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24803665, 15985475, 16263833, 21407260, 14974085, 18372317, 15834506, 19077116, 12634870, 11992261, 24183200, 24037001, 22488759, 21784453, 16377799, 11704759, 30541462, 30417923, 30050098, 29907801, 31560489, 32546215, 33300679, 34006472, 33728303) -

Sep 14, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Pathogenic:2

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 282 of the PTPN11 protein (p.Ile282Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 15834506, 19077116, 21407260). ClinVar contains an entry for this variant (Variation ID: 40525). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 14974085, 15834506, 18372317). For these reasons, this variant has been classified as Pathogenic. -

Apr 25, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PTPN11 c.844A>G variant affects a conserved nucleotide, resulting in an amino acid change from Ile to Val in functionally important protein tyrosine phosphatase (PTP) domain. 2/4 in-silico tools predict this variant to be damaging, and published functional studies are consistent with the variant being an activating mutation; gain of function is a known molecular mechanism in Noonan Syndrome. This variant was not found in approximately 118834 control chromosomes; however, the variant is a known recurrent pathogenic mutation causing Noonan Syndrome reported in the literature. It has been reported in sporadic as well as familial Noonan cases. Additionally, multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic. -

Neurodevelopmental abnormality

Pathogenic:1

Oct 28, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LEOPARD syndrome 1;C4551602:Noonan syndrome 1

Pathogenic:1

Jul 07, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTPN11-related disorder

Pathogenic:1

Aug 22, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP2 -

Noonan syndrome

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines

Pathogenic:1

May 09, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile282Val variant in PTPN11 has been reported in >20 individuals with clin ical features of Noonan syndrome or LEOPARD syndrome (Tartaglia 2001, Tartaglia 2002, Mustane 2003, Binder 2005, Tartaglia 2006, Jongmans 2011, LMM unpublished data), and is absent from large population studies. In addition, functional evid ence suggests that this variant increases the activity of the PTPN11 protein, wh ich is consistent with other pathogenic variants in PTPN11 (Fragale 2004, Tartag lia 2006, Martinelli 2008). In summary, this variant meets our criteria to be cl assified as pathogenic for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM). -

Cardiovascular phenotype

Pathogenic:1

Jun 05, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.844A>G (p.I282V) alteration is located in coding exon 7 of the PTPN11 gene. This alteration results from a A to G substitution at nucleotide position 844, causing the isoleucine (I) at amino acid position 282 to be replaced by a valine (V). This variant is unlikely to be causative of Metachondromatosis; however, it would be expected to be causative of PTPN11-related RASopathy based on mechanism of disease. Based on data from gnomAD, the G allele has an overall frequency of 0.0006571% (1/152190) total alleles studied. The highest observed frequency was 0.006548% (1/15272) of Latino/Admixed American alleles. This alteration has been reported in multiple patients in the literature with Noonan syndrome (Tartaglia, 2001; Musante, 2003; Tartaglia, 2006) and as de novo in multiple individuals with clinical features consistent with PTPN11-related RASopathy (Swarts, 2022; DECIPHER v.9.32). Another alteration at the same codon, c.846C>G (p.I282M), has been detected in individuals who have a phenotype consistent with Noonan syndrome (Atik, 2016; Kruszka, 2017; Chinton, 2019; Castellanos, 2020). This amino acid position is highly conserved in available vertebrate species. The p.I282 amino acid is located in the PTP (catalytic) domain of the SHP-2 protein. It contributes to the hydrophobic region binding the pY-phenyl ring and interacts with N-SH2 domain residues (Tartaglia, 2006). The SHP-2 protein switches between inactive and active conformations, depending on its binding to phosphotyrosyl (pY)–containing signaling partners. In the unliganded inactive conformation, the N-SH2 domain interacts extensively with the PTP domain, blocking the active site. Functional analysis demonstrated that the p.I282V alteration perturbs the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation. This in combination with an increased intrinsic catalytic activity results in a 3-fold upregulation of SHP-2 activity (Martinelli, 2008). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1

Pathogenic:1

Dec 10, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in at least 7 individuals with a clinical diagnosis or suspicion of Noonan syndrome and other RASopathies, including 2 reported de novo cases, and segregating with disease in at least 1 affected family member (selected publications: Tartaglia 2001 PMID:11704759; Jongmans 2011 PMID:21407260; Bessis 2019 PMID:30417923; Lores 2020 PMID:33300679). This variant is present in 0.007% (1/15272) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12 112473031 A G?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40525). Of note, this variant occurs in a gene with a high burden of pathogenic missense variants, consistent with a gain of function mechanism (Gelb 2018 PMID:29493581). In vitro functional studies predict that this variant will impact the protein (Fragale 2004 PID:14974085; Martinelli 2008 PMID:18372317). However, these studies may not accurately represent in vivo biological function. Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Benign

0.0096

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

.;.;D

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

-0.043

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.88

N;N;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D;.

Sift4G

Benign

0.18

T;T;T

Polyphen

0.60

P;B;.

Vest4

0.74

MutPred

0.90

Loss of catalytic residue at P284 (P = 0.0303);Loss of catalytic residue at P284 (P = 0.0303);Loss of catalytic residue at P284 (P = 0.0303);

MVP

0.97

MPC

0.70

ClinPred

0.93

GERP RS

5.7

Varity_R

0.75

gMVP

0.47

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