rs1553798675

Variant names:

• chr3-192335441-C-T
• rs1553798675
• NM_004113.6:c.148G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_004113.6(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 NM_004113.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.56
• Publications: 1 publications found

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]

FGF12 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 47

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 522854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF12	NM_004113.6	c.148G>A	p.Gly50Ser	missense_variant	Exon 4 of 6	ENST00000445105.7	NP_004104.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF12	ENST00000445105.7	c.148G>A	p.Gly50Ser	missense_variant	Exon 4 of 6	1	NM_004113.6	ENSP00000393686.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 47 Pathogenic:5

Nov 29, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2017

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2020

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Aug 23, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGF12: PS2, PM2, PS4:Moderate, PS3:Supporting -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522854). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FGF12 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

FGF12-related disorder Pathogenic:1

Oct 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	.;D;.;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.5	.;L;.;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.045	D;T;D;T;T;D
Sift4G	Uncertain	0.051	T;D;T;D;T;T
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.85
MutPred		0.46		.;Loss of catalytic residue at L113 (P = 0.1155);.;.;.;.;
MVP		0.89
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.63
gMVP		0.55
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553798675; hg19: chr3-192053230;