rs1553798675

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004715542: "In vitro analysis suggested that p.Gly112Ser modified the biophysical kinetics of ion channel activity (Seiffert et al. 2022. PubMed ID: 36029553)."". 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:10
• Conservation: PhyloP100: 7.56
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004715542: "In vitro analysis suggested that p.Gly112Ser modified the biophysical kinetics of ion channel activity (Seiffert et al. 2022. PubMed ID: 36029553)."
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004113.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF12	NM_004113.6	MANE Select	c.148G>A	p.Gly50Ser	missense	Exon 4 of 6	NP_004104.3
	FGF12	NM_021032.5		c.334G>A	p.Gly112Ser	missense	Exon 3 of 5	NP_066360.1	P61328-1
	FGF12	NM_001377293.1		c.76G>A	p.Gly26Ser	missense	Exon 3 of 5	NP_001364222.1	A0A804HIN2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF12	ENST00000445105.7	TSL:1 MANE Select	c.148G>A	p.Gly50Ser	missense	Exon 4 of 6	ENSP00000393686.1	P61328-2
	FGF12	ENST00000454309.7	TSL:1	c.334G>A	p.Gly112Ser	missense	Exon 3 of 5	ENSP00000413496.2	P61328-1
	FGF12	ENST00000450716.5	TSL:5	c.148G>A	p.Gly50Ser	missense	Exon 4 of 6	ENSP00000397635.1	P61328-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Developmental and epileptic encephalopathy, 47 (6)
3	-	-	not provided (3)
1	-	-	FGF12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.045	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	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;