chr8-38424690-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_023110.3(FGFR1):c.755C>G(p.Pro252Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,640 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists 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 both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

FGFR1 links:

ENSG00000255201 (HGNC:):

ENSG00000255201 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 8-38424690-G-C is Pathogenic according to our data. Variant chr8-38424690-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38424690-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.755C>G	p.Pro252Arg	missense_variant	Exon 7 of 18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 link	c.755C>G	p.Pro252Arg	missense_variant	Exon 7 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.749C>G	p.Pro250Arg	missense_variant	Exon 7 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.749C>G	p.Pro250Arg	missense_variant	Exon 8 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.749C>G	p.Pro250Arg	missense_variant	Exon 7 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.488C>G	p.Pro163Arg	missense_variant	Exon 6 of 17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.482C>G	p.Pro161Arg	missense_variant	Exon 5 of 16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.482C>G	p.Pro161Arg	missense_variant	Exon 6 of 17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.*446C>G		non_coding_transcript_exon_variant	Exon 6 of 12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 link	n.*446C>G		3_prime_UTR_variant	Exon 6 of 12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248744

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459640

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725616

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pfeiffer syndrome

Pathogenic:4

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 27, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PS3; PS4; PM2; PP1; PP3; PP5 -

Jun 17, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with a significantly increased bindings affinity for endogenous ligands; additionally functional studies in an animal model demonstrate a damaging effect potentially via aberrant activation of downstream target Cbfa1 (Ibrahimi et al., 2004; Zhou et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23329143, 27065010, 7795583, 24127277, 10861678, 14564217, 7874169, 16957473, 24497711, 10942429, 31837199, 31016899, 32510873, 31167513, 32139749, 30207415, 34159400, 31785789, 14613973, 25251565) -

Jackson-Weiss syndrome

Pathogenic:2

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 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: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 [HH2] (MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (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 (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 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 has been observed in over ten individuals with FGFR1-related conditions. It has mainly been reported in individuals with Pfeiffer syndrome (MIM#101600) but has been observed in one individual with Jackson-Weiss syndrome (MIM#123150) (ClinVar, LOVD, DECIPHER, PMIDs: 24127277, 31837199, 1456217, 10861678). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

FGFR1-related disorder

Pathogenic:1

Oct 28, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP1, PP2, PP3 -

Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

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

PS3,PS4,PP1,PP3 -

Pfeiffer syndrome;C0406612:Encephalocraniocutaneous lipomatosis;C0432122:Trigonocephaly 1;C0432283:Osteoglophonic dysplasia;C0795998:Jackson-Weiss syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia;C1845146:Hartsfield-Bixler-Demyer syndrome

Pathogenic:1

Jul 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

Mar 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 10942429, 14613973). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 16279). This missense change has been observed in individuals with Pfeiffer syndrome (PMID: 7795583, 7874169, 10861678, 14564217, 16957473, 24127277, 24497711, 25251565). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909627, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the FGFR1 protein (p.Pro252Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

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

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.91

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

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.7

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

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.1

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

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.19

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

Polyphen

1.0

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

Vest4

0.93

MutPred

0.71

.;.;Loss of glycosylation at P252 (P = 0.0323);.;.;Loss of glycosylation at P252 (P = 0.0323);.;.;.;.;.;.;.;Loss of glycosylation at P252 (P = 0.0323);

MVP

0.93

MPC

2.6

ClinPred

0.99

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.95

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