8-38426158-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The ENST00000447712.7(FGFR1):​c.709G>A​(p.Gly237Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G237D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR1
ENST00000447712.7 missense

Scores

13
5
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a domain Ig-like C2-type 2 (size 88) in uniprot entity FGFR1_HUMAN there are 40 pathogenic changes around while only 1 benign (98%) 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 chr8-38426157-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2505415.Status of the report is criteria_provided_single_submitter, 1 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, 0.954
PP5
Variant 8-38426158-C-T is Pathogenic according to our data. Variant chr8-38426158-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38426158-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FGFR1NM_023110.3 linkuse as main transcriptc.709G>A p.Gly237Ser missense_variant 6/18 ENST00000447712.7 NP_075598.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FGFR1ENST00000447712.7 linkuse as main transcriptc.709G>A p.Gly237Ser missense_variant 6/181 NM_023110.3 ENSP00000400162 P4P11362-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 18, 2006- -
Likely pathogenic, criteria provided, single submitterresearchReproductive Endocrine Unit, Massachusetts General HospitalMay 04, 2023- -
FGFR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 22, 2022Variant summary: FGFR1 c.709G>A (p.Gly237Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250914 control chromosomes (gnomAD and publication data). c.709G>A has been reported in the literature in individuals affected with idiopathic hypogonadotropic hypogonadism as well as in two unaffected individuals (Pitteloud_2006, Shaw_2011, Wang_2014, Wang_2017, Men_2019). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant results in inhibiting proper folding of the FGFR1 and likely leading to the loss of cell-surface expression of FGFR1 (Pitteloud_2006). Additionally, another missense variant at the same codon, G237D, has been found in patients with Kallmann syndrome and segregated with the disease in one family (PMID: 16764984), indicating this residue is critical for FGFR1 protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
.;.;D;T;.;.;.;.;.;.;T;.;T;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Pathogenic
3.2
.;.;M;.;.;M;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.3
D;D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;D;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.016
D;D;D;D;D;D;D;D;D;D;D;D;.;.
Polyphen
0.98
D;D;D;D;.;D;D;P;D;P;.;D;.;.
Vest4
0.97
MutPred
0.84
.;.;Gain of glycosylation at G237 (P = 0.0682);.;.;Gain of glycosylation at G237 (P = 0.0682);.;.;.;.;.;.;.;Gain of glycosylation at G237 (P = 0.0682);
MVP
0.93
MPC
2.1
ClinPred
0.99
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.94
gMVP
0.82

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.

Other links and lift over

dbSNP: rs121909635; hg19: chr8-38283676; API