chr8-38424696-C-G

Position:

• chr8-38424696-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The ENST00000447712.7(FGFR1):​c.749G>C​(p.Arg250Pro) 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. R250Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 ENST00000447712.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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, 0.945
• PP5: Variant 8-38424696-C-G is Pathogenic according to our data. Variant chr8-38424696-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 235084.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.749G>C	p.Arg250Pro	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>C	p.Arg250Pro	missense_variant	7/18	1	NM_023110.3	ENSP00000400162	P4
	ENST00000528407.1	n.388-1254C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lobar holoprosencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics, CHU Rennes

Apr 13, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2023

Not observed at significant frequency 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: 27363716) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;D;T;.;.;.;.;.;.;T;.;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.3	.;.;L;.;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.2	D;D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	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;.;.
Polyphen		0.99	D;D;D;D;.;D;D;D;D;D;.;D;.;.
Vest4		0.82
MutPred		0.84		.;.;Gain of glycosylation at R250 (P = 0.1072);.;.;Gain of glycosylation at R250 (P = 0.1072);.;.;.;.;.;.;.;Gain of glycosylation at R250 (P = 0.1072);
MVP		0.93
MPC		3.1
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.97

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: rs121909645; hg19: chr8-38282214;