8-38424696-C-T

Position:

• chr8-38424696-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_023110.3(FGFR1):​c.749G>A​(p.Arg250Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• 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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.959
• PP5: Variant 8-38424696-C-T is Pathogenic according to our data. Variant chr8-38424696-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38424696-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.749G>A	p.Arg250Gln	missense_variant	7/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.749G>A	p.Arg250Gln	missense_variant	7/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.743G>A	p.Arg248Gln	missense_variant	7/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.743G>A	p.Arg248Gln	missense_variant	8/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.743G>A	p.Arg248Gln	missense_variant	7/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.482G>A	p.Arg161Gln	missense_variant	6/17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.476G>A	p.Arg159Gln	missense_variant	5/16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.476G>A	p.Arg159Gln	missense_variant	6/17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*440G>A		non_coding_transcript_exon_variant	6/12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*440G>A		3_prime_UTR_variant	6/12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	research	Reproductive Endocrine Unit, Massachusetts General Hospital	May 04, 2023	- -
risk factor, no assertion criteria provided	literature only	OMIM	May 02, 2013	- -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

ClinVar contains an entry for this variant (Variation ID: 16303). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 18596921, 19820032). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of Kallmann syndrome (PMID: 18596921, 20696889, 31748124, 33442024). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 250 of the FGFR1 protein (p.Arg250Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;.;D;T;.;.;.;.;.;.;T;.;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.4	.;.;M;.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;T;D;T;T;D;.;.
Polyphen		0.97	D;P;P;D;.;P;P;P;P;P;.;P;.;.
Vest4		0.85
MutPred		0.89		.;.;Loss of glycosylation at P252 (P = 0.1206);.;.;Loss of glycosylation at P252 (P = 0.1206);.;.;.;.;.;.;.;Loss of glycosylation at P252 (P = 0.1206);
MVP		0.94
MPC		2.7
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909645; hg19: chr8-38282214; COSMIC: COSV58335636; COSMIC: COSV58335636;