rs1554564353

Positions:

• chr8-38426242-G-A
• chr8-38426242-G-C
• chr8-38426242-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The ENST00000447712.7(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 ENST00000447712.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a strand (size 2) in uniprot entity FGFR1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000447712.7
• 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 gene, where missense usually causes diseases (based on misZ statistic), FGFR1. . Gene score misZ 2.4852 (greater than the threshold 3.09). Trascript score misZ 4.2642 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.625C>T	p.Arg209Cys	missense_variant	6/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.625C>T	p.Arg209Cys	missense_variant	6/18	1	NM_023110.3	ENSP00000400162	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	-	- -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Dec 16, 2016	- -

FGFR1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
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	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.7	.;.;H;.;.;H;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
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	D
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

Other links and lift over

dbSNP: rs1554564353; hg19: chr8-38283760; COSMIC: COSV58346753; COSMIC: COSV58346753;