11-60462451-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152866.3(MS4A1):c.77G>T(p.Gly26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MS4A1
NM_152866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.26

Variant links:

Genes affected

MS4A1 (HGNC:7315): (membrane spanning 4-domains A1) This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants which encode the same protein. [provided by RefSeq, Jul 2008]

MS4A1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044367343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MS4A1	NM_152866.3 link	c.77G>T	p.Gly26Val	missense_variant	Exon 3 of 8	ENST00000345732.9	NP_690605.1	P11836-1A0A024R507
MS4A1	NM_021950.4 link	c.77G>T	p.Gly26Val	missense_variant	Exon 2 of 7		NP_068769.2	P11836-1A0A024R507
MS4A1	NM_152867.2 link	c.77G>T	p.Gly26Val	missense_variant	Exon 2 of 7		NP_690606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MS4A1	ENST00000345732.9 link	c.77G>T	p.Gly26Val	missense_variant	Exon 3 of 8	1	NM_152866.3	ENSP00000314620.7		P11836-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249742

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135172

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with MS4A1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 26 of the MS4A1 protein (p.Gly26Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.057

DANN

Benign

0.28

DEOGEN2

Benign

0.12

T;T;T;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.53

.;T;.;T;T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.044

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;.;N;N;.;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.98

N;N;N;N;N;N

REVEL

Benign

0.0020

Sift

Benign

0.30

T;T;T;T;T;T

Sift4G

Benign

0.31

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;.;.;B

Vest4

0.15

MutPred

0.19

Loss of glycosylation at S25 (P = 0.0452);Loss of glycosylation at S25 (P = 0.0452);Loss of glycosylation at S25 (P = 0.0452);Loss of glycosylation at S25 (P = 0.0452);.;Loss of glycosylation at S25 (P = 0.0452);

MVP

0.33

MPC

0.042

ClinPred

0.16

GERP RS

-2.3

Varity_R

0.051

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over