8-38414279-C-T

Position:

• chr8-38414279-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_023110.3(FGFR1):​c.2059G>A​(p.Gly687Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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. G687?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a helix (size 15) in uniprot entity FGFR1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chr8-38414279-C-K is described in Lovd as [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, 0.993
• PP5: Variant 8-38414279-C-T is Pathogenic according to our data. Variant chr8-38414279-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38414279-C-T is described in Lovd as [Pathogenic]. Variant chr8-38414279-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.2059G>A	p.Gly687Arg	missense_variant	16/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.2059G>A	p.Gly687Arg	missense_variant	16/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.2053G>A	p.Gly685Arg	missense_variant	16/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.2053G>A	p.Gly685Arg	missense_variant	17/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.2053G>A	p.Gly685Arg	missense_variant	16/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1792G>A	p.Gly598Arg	missense_variant	15/17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1792G>A	p.Gly598Arg	missense_variant	14/16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1786G>A	p.Gly596Arg	missense_variant	15/17	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Reproductive Endocrine Unit, Massachusetts General Hospital	May 04, 2023	The variant has been classified as P3b based on the variant meeting the following ACMG Criteria: PM2,PP3,PM1,PP1,PP2,PP4. -
Pathogenic, no assertion criteria provided	research	Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	-	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FGFR1: PM1, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Published functional studies demonstrate this variant damages normal FGFR1 function (Wang et al., 2020); Not observed 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: 31067328, 32666525, 23329143, 26207952, 23643382, 25636053, 30098700, 33548149, 25226293, 30430143, 27502037, 15845591) -

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

FGFR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2023

The FGFR1 c.2059G>A variant is predicted to result in the amino acid substitution p.Gly687Arg. This variant (also described as p.Gly685Arg) has been reported in multiple unrelated individuals with hypogonadotropic hypogonadism or Kallmann syndrome and segregated with disease in several families (Sato. 2005. PubMed ID: 15845591; Table S3, Miraoui. 2013. PubMed ID: 23643382; Choi. 2015. PubMed ID: 26207952; Quaynor. 2016. PubMed ID: 27502037; Table S3, Zhou. 2018. PubMed ID: 30098700; Wang. 2020. PubMed ID: 32666525; Nie. 2021. PubMed ID: 33548149). This variant impaired tyrosine kinase activity in an in vitro functional assay (Wang. 2020. PubMed ID: 32666525). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar this variant is listed as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/180160/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.1	.;.;H;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.0	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;D;D;.;.
Vest4		1.0
MutPred		0.94		.;.;Loss of catalytic residue at V688 (P = 0.0291);.;.;.;.;.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs727505376; hg19: chr8-38271797; COSMIC: COSV100248222; COSMIC: COSV100248222;