rs1554564353

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_023110.3(FGFR1):c.625C>T(p.Arg209Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 6.29

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a domain Ig-like C2-type 2 (size 88) in uniprot entity FGFR1_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) in NM_023110.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-38426241-C-T is described in Lovd as [Likely_pathogenic].

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, 0.896

PP5

Variant 8-38426242-G-A is Pathogenic according to our data. Variant chr8-38426242-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548670.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-38426242-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-38426242-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.625C>T	p.Arg209Cys	missense_variant	Exon 6 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.625C>T	p.Arg209Cys	missense_variant	Exon 6 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.619C>T	p.Arg207Cys	missense_variant	Exon 6 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.619C>T	p.Arg207Cys	missense_variant	Exon 7 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.619C>T	p.Arg207Cys	missense_variant	Exon 6 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.358C>T	p.Arg120Cys	missense_variant	Exon 5 of 17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.352C>T	p.Arg118Cys	missense_variant	Exon 4 of 16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.352C>T	p.Arg118Cys	missense_variant	Exon 5 of 17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.*316C>T		non_coding_transcript_exon_variant	Exon 5 of 12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 link	n.*316C>T		3_prime_UTR_variant	Exon 5 of 12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:2

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 16, 2016

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

FGFR1-related disorder

Pathogenic:1

Sep 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FGFR1 c.625C>T variant is predicted to result in the amino acid substitution p.Arg209Cys. This variant has been previously reported in individuals with Kallmann syndrome with or without cleft lip/palate (Supplementary table 2, Dodé et al 2009. PubMed ID: 18985070; reported as NM 001174066: c.358C>T, p.R120C in case 3, Xu et al. 2015. PubMed ID: 26199944). This variant was also reported as inherited from an unaffected father in an individual with hypogonadotropic hypogonadism (Akkuş et al. 2016. PubMed ID: 28008864). In addition, the c.625C>T (p.Arg209Cys) variant was identified in an individual with idiopathic hypogonadotropic hypogonadism, his affected uncle and unaffected father (Wang et al 2020. PubMed ID: 32666525). In vitro functional studies using a reporter gene assay found a modest decrease in expression compared to wild type isoform (Wang et al 2020. PubMed ID: 32666525), leading the authors to hypothesize the presence of other unidentified gene variant(s) associated with IHH (Wang et al 2020. PubMed ID: 32666525). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare; and, in Clinvar it is interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/548670/). In summary, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.90

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

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.7

.;.;H;.;.;H;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.8

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

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.90

MutPred

0.65

.;.;Loss of MoRF binding (P = 0.0019);.;.;Loss of MoRF binding (P = 0.0019);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0019);.;.;

MVP

0.91

MPC

2.9

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

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