3-192144049-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004113.6(FGF12):c.506C>T(p.Thr169Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,332 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGF12 NM_004113.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2934937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF12	NM_004113.6	c.506C>T	p.Thr169Ile	missense_variant	6/6	ENST00000445105.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF12	ENST00000445105.7	c.506C>T	p.Thr169Ile	missense_variant	6/6	1	NM_004113.6	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461332 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 231 of the FGF12 protein (p.Thr231Ile). This variant has not been reported in the literature in individuals affected with FGF12-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.53	N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.38	B;P;B;.
Vest4		0.53
MutPred		0.15		.;Loss of phosphorylation at T231 (P = 0.0319);.;.;
MVP		0.87
MPC		1.2
ClinPred		0.64	D
GERP RS		5.8
Varity_R		0.13
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-191861838;