8-38428420-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_023110.3(FGFR1):c.374C>T(p.Ser125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
FGFR1
NM_023110.3 missense
NM_023110.3 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 6.19
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a region_of_interest Disordered (size 34) in uniprot entity FGFR1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_023110.3
PM2
Very rare variant in population databases, with high coverage;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.4134978).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGFR1 | NM_023110.3 | c.374C>T | p.Ser125Leu | missense_variant | 4/18 | ENST00000447712.7 | NP_075598.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR1 | ENST00000447712.7 | c.374C>T | p.Ser125Leu | missense_variant | 4/18 | 1 | NM_023110.3 | ENSP00000400162.2 | ||
FGFR1 | ENST00000397091.9 | c.374C>T | p.Ser125Leu | missense_variant | 4/18 | 1 | ENSP00000380280.5 | |||
FGFR1 | ENST00000397108.8 | c.374C>T | p.Ser125Leu | missense_variant | 5/19 | 1 | ENSP00000380297.4 | |||
FGFR1 | ENST00000397113.6 | c.374C>T | p.Ser125Leu | missense_variant | 4/18 | 2 | ENSP00000380302.2 | |||
FGFR1 | ENST00000356207.9 | c.107C>T | p.Ser36Leu | missense_variant | 3/17 | 1 | ENSP00000348537.5 | |||
FGFR1 | ENST00000397103.5 | c.107C>T | p.Ser36Leu | missense_variant | 2/16 | 5 | ENSP00000380292.1 | |||
FGFR1 | ENST00000326324.10 | c.107C>T | p.Ser36Leu | missense_variant | 3/17 | 1 | ENSP00000327229.6 | |||
FGFR1 | ENST00000487647.5 | n.*65C>T | non_coding_transcript_exon_variant | 3/12 | 1 | ENSP00000435254.1 | ||||
FGFR1 | ENST00000487647.5 | n.*65C>T | 3_prime_UTR_variant | 3/12 | 1 | ENSP00000435254.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 245296Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133350
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1460564Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 726534
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypogonadotropic hypogonadism 2 with or without anosmia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Reproductive Endocrine Unit, Massachusetts General Hospital | May 04, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27896051, 25157968, 17344846, 33081025, 33268819) - |
Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 09, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 376297). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. This variant is present in population databases (rs121913473, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 125 of the FGFR1 protein (p.Ser125Leu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;T;.;.;.;.;.;.;T;.;T;.;T;D;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;N;N;.;.;N;N;.;.;.;.;N;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;D;D;D;N;D;N;D;D;D;D;D;N;N
REVEL
Uncertain
Sift
Benign
D;T;D;.;T;D;T;T;D;T;D;T;D;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T;T;.;.;T;.;.
Polyphen
P;B;B;B;.;B;B;B;B;B;.;B;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at