8-38417331-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_023110.3(FGFR1):c.1638C>A(p.Asn546Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:2

Conservation

PhyloP100: 2.11

Publications

197 publications found

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 Gene-Disease associations (from GenCC):

encephalocraniocutaneous lipomatosis
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hartsfield-Bixler-Demyer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
hypogonadotropic hypogonadism 2 with or without anosmia
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
osteoglophonic dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Pfeiffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Pfeiffer syndrome type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Jackson-Weiss syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated trigonocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 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 Hartsfield-Bixler-Demyer syndrome, Pfeiffer syndrome type 1, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism 2 with or without anosmia, osteoglophonic dysplasia, isolated trigonocephaly, septooptic dysplasia, Pfeiffer syndrome, tooth agenesis, hypogonadotropic hypogonadism, Kallmann syndrome, holoprosencephaly, Jackson-Weiss syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 8-38417331-G-T is Pathogenic according to our data. Variant chr8-38417331-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 224896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.1638C>A	p.Asn546Lys	missense_variant	Exon 12 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGFR1	ENST00000447712.7 link	c.1638C>A	p.Asn546Lys	missense_variant	Exon 12 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9 link	c.1632C>A	p.Asn544Lys	missense_variant	Exon 12 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8 link	c.1632C>A	p.Asn544Lys	missense_variant	Exon 13 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6 link	c.1632C>A	p.Asn544Lys	missense_variant	Exon 12 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9 link	c.1371C>A	p.Asn457Lys	missense_variant	Exon 11 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5 link	c.1371C>A	p.Asn457Lys	missense_variant	Exon 10 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10 link	c.1365C>A	p.Asn455Lys	missense_variant	Exon 11 of 17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5 link	n.*1329C>A		non_coding_transcript_exon_variant	Exon 11 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5 link	n.*1329C>A		3_prime_UTR_variant	Exon 11 of 12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Encephalocraniocutaneous lipomatosis

Pathogenic:4Other:1

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

An FGFR1 c.1638C>A (p.Asn546Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant occurs at a mutational hotspot and has been reported in numerous individuals with encephalocraniocutaneous lipomatosis (Kupsik M et al., PMID: 23819449; Nowaczyk MJ et al., PMID: 10766980; Bennett JT et al., PMID: 26942290; Kordacka J et al., PMID: 31173478; Chacon-Camacho OF et al., PMID: 30891959; Liu J et al., PMID: 31856217). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. It has been reported as a somatic pathogenic variant in the ClinVar database by two submitters (ClinVar ID: 224896) and has been identified in numerous cancer cases, mainly CNS tumors, in the cancer database COSMIC (COSV58329537). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to FGFR1 function. In support of this prediction, functional studies show that over-expression of the FGFR1 p.Asn546Lys protein results in higher nuclear localization compared to wild-type protein, increased cellular invasion and cologenicity, and failure to respond to inhibitory treatments through activation of ERK, STAT3 and AKT pathways (Cimmino F et al., PMID: 35488346; Agelopoulos K et al., PMID: 26179511; Jones DT et al., PMID: 23817572; Ng PK et al., PMID: 29533785). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the FGFR1 c.1638C>A (p.Asn546Lys) variant is classified as pathogenic. -

Aug 11, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 25, 2017

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Rosette-forming glioneuronal tumor

Pathogenic:1

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

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

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.94

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

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

-0.28

.;.;N;.;.;.;.;.;.;.

PhyloP100

2.1

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.77

.;.;Gain of methylation at N546 (P = 0.0047);.;.;.;.;.;.;.;

MVP

0.93

MPC

2.2

ClinPred

1.0

GERP RS

3.8

Varity_R

0.99

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over