11-60503728-G-A

Position:

• chr11-60503728-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000016913.8(MS4A12):​c.499G>A​(p.Val167Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MS4A12 ENST00000016913.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.339

Genes affected

MS4A12 (HGNC:13370): (membrane spanning 4-domains A12) The protein encoded by this gene is a cell surface protein found primarily in the apical membrane of colonocytes. Silencing of this gene in colon cancer cells inhibits the proliferation, cell motility, and chemotactic invasion of cells. This gene is part of a cluster of similar genes found on chromosome 11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09756419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MS4A12	NM_017716.3	c.499G>A	p.Val167Ile	missense_variant	5/7	ENST00000016913.8	NP_060186.2
MS4A12	NM_001164470.2	c.361G>A	p.Val121Ile	missense_variant	4/6		NP_001157942.1
MS4A12	XM_011545117.3	c.499G>A	p.Val167Ile	missense_variant	6/8		XP_011543419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MS4A12	ENST00000016913.8	c.499G>A	p.Val167Ile	missense_variant	5/7	1	NM_017716.3	ENSP00000016913.4
MS4A12	ENST00000537076.5	c.361G>A	p.Val121Ile	missense_variant	4/6	5		ENSP00000440424.1
MS4A12	ENST00000526784.5	c.361G>A	p.Val121Ile	missense_variant	4/5	3		ENSP00000431959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.499G>A (p.V167I) alteration is located in exon 5 (coding exon 4) of the MS4A12 gene. This alteration results from a G to A substitution at nucleotide position 499, causing the valine (V) at amino acid position 167 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.3
DANN	Benign	0.83
DEOGEN2	Benign	0.0010	.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	.;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.088
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.64	.;.;P
Vest4		0.096, 0.075
MutPred		0.53		.;.;Loss of catalytic residue at V167 (P = 0.021);
MVP		0.061
MPC		0.089
ClinPred		0.15	T
GERP RS		-2.4
Varity_R		0.040

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

LitVar

Other links and lift over

dbSNP: rs1590863027; hg19: chr11-60271201;