Genetic Variant MS4A1:p.Met17Ile (chr11-60462425-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152866.3(MS4A1):c.51G>A(p.Met17Ile) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M17T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MS4A1
NM_152866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.101

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
immunodeficiency, common variable, 5
Inheritance: AR, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

MS4A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04441023).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152866.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MS4A1	NM_152866.3	MANE Select	c.51G>A	p.Met17Ile	missense	Exon 3 of 8	NP_690605.1	P11836-1
MS4A1	NM_021950.4		c.51G>A	p.Met17Ile	missense	Exon 2 of 7	NP_068769.2
MS4A1	NM_152867.2		c.51G>A	p.Met17Ile	missense	Exon 2 of 7	NP_690606.1	P11836-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MS4A1	ENST00000345732.9	TSL:1 MANE Select	c.51G>A	p.Met17Ile	missense	Exon 3 of 8	ENSP00000314620.7	P11836-1
MS4A1	ENST00000389939.2	TSL:1	c.51G>A	p.Met17Ile	missense	Exon 1 of 6	ENSP00000374589.2	P11836-1
MS4A1	ENST00000532073.5	TSL:1	c.51G>A	p.Met17Ile	missense	Exon 2 of 7	ENSP00000433519.1	E9PKH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250482

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.7

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.087

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.48

M_CAP

Benign

0.0017

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

-0.10

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.33

REVEL

Benign

0.073

Sift

Benign

0.59

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.14

MutPred

0.23

Loss of solvent accessibility (P = 0.0036)

MVP

0.18

MPC

0.039

ClinPred

0.15

GERP RS

2.5

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.056

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over