3-192144106-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004113.6(FGF12):c.449C>T(p.Ser150Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S150S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF12	NM_004113.6	c.449C>T	p.Ser150Leu	missense_variant	6/6	ENST00000445105.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF12	ENST00000445105.7	c.449C>T	p.Ser150Leu	missense_variant	6/6	1	NM_004113.6	A1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251166 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460262 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74408

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

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, 2023

ClinVar contains an entry for this variant (Variation ID: 1355797). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 212 of the FGF12 protein (p.Ser212Leu). This variant is present in population databases (rs368025154, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FGF12-related conditions. 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 FGF12 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.95	P;D;P;.;.
Vest4		0.69
MVP		0.87
MPC		1.5
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.66
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368025154; hg19: chr3-191861895; COSMIC: COSV53151116;