rs1553798675
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000445105.7(FGF12):c.148G>A(p.Gly50Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G50G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
FGF12
ENST00000445105.7 missense
ENST00000445105.7 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 7.56
Genes affected
FGF12 (HGNC:3668): (fibroblast growth factor 12) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth, and invasion. This growth factor lacks the N-terminal signal sequence present in most of the FGF family members, but it contains clusters of basic residues that have been demonstrated to act as a nuclear localization signal. When transfected into mammalian cells, this protein accumulated in the nucleus, but was not secreted. The specific function of this gene has not yet been determined. [provided by RefSeq, Dec 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-192335441-C-T is Pathogenic according to our data. Variant chr3-192335441-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-192335441-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGF12 | NM_004113.6 | c.148G>A | p.Gly50Ser | missense_variant | 4/6 | ENST00000445105.7 | NP_004104.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGF12 | ENST00000445105.7 | c.148G>A | p.Gly50Ser | missense_variant | 4/6 | 1 | NM_004113.6 | ENSP00000393686 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 47 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 03, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Mar 26, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Nov 29, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The FGF12 c.334G>A variant has been reported in heterozygous state in individuals affected with Developmental and epileptic encephalopathy 47 (Trivisano M et. al., 2020; Tian Q et al., 2021). The p.Gly112Ser variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid Gly at position 112 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Gly112Ser in FGF12 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Dec 09, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 112 of the FGF12 protein (p.Gly112Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGF12-related conditions (PMID: 31292943, 32645220; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522854). 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) performed at Invitae indicates that this missense variant is not expected to disrupt FGF12 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31292943, 32645220, 34020858, 27872899, Seiffert2021[article]) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | FGF12: PS2, PM2, PS4:Moderate, PS3:Supporting - |
FGF12-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 26, 2023 | The FGF12 c.334G>A variant is predicted to result in the amino acid substitution p.Gly112Ser. FGF12 is also referred to as FHF1 in the literature. This variant has been reported in three individuals with developmental and epileptic encephalopathy; in two subjects the variant was de novo and in one it was inherited (Paprocka et al. 2019. PubMed ID: 31292943; Trivisano et al. 2020. PubMed ID: 32645220; Seiffert et al. 2022. PubMed ID: 36029553). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. In vitro analysis suggested that p.Gly112Ser modified the biophysical kinetics of ion channel activity (Seiffert et al. 2022. PubMed ID: 36029553). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;L;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
D;T;D;T;T;D
Sift4G
Uncertain
T;D;T;D;T;T
Polyphen
D;D;D;.;.;.
Vest4
MutPred
0.46
.;Loss of catalytic residue at L113 (P = 0.1155);.;.;.;.;
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at