chr11-60067086-T-A

Position:

chr11-60067086-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006138.5(MS4A3):c.487T>A(p.Cys163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,608,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MS4A3
NM_006138.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.72

Variant links:

Genes affected

MS4A3 (HGNC:7317): (membrane spanning 4-domains A3) This gene encodes a member of the membrane-spanning 4A gene family. Members of this 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 family member likely plays a role in signal transduction and may function as a subunit associated with receptor complexes. The gene encoding this protein is localized to 11q12, among a cluster of related family members. Alternative splicing may result in multiple transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

MS4A3 links:

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ACMG classification

Classification made for transcript

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=0.40751785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MS4A3	NM_006138.5 linkuse as main transcript	c.487T>A	p.Cys163Ser	missense_variant	5/7	ENST00000278865.8
MS4A3	NM_001031809.2 linkuse as main transcript	c.349T>A	p.Cys117Ser	missense_variant	4/6
MS4A3	NM_001031666.2 linkuse as main transcript	c.118T>A	p.Cys40Ser	missense_variant	3/5
MS4A3	XM_011545363.4 linkuse as main transcript	c.307T>A	p.Cys103Ser	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MS4A3	ENST00000278865.8 linkuse as main transcript	c.487T>A	p.Cys163Ser	missense_variant	5/7	1	NM_006138.5	P1	Q96HJ5-1
MS4A3	ENST00000358152.6 linkuse as main transcript	c.349T>A	p.Cys117Ser	missense_variant	4/6	5			Q96HJ5-2
MS4A3	ENST00000395032.6 linkuse as main transcript	c.118T>A	p.Cys40Ser	missense_variant	3/5	2			Q96HJ5-3
MS4A3	ENST00000525686.1 linkuse as main transcript	c.*162T>A		3_prime_UTR_variant, NMD_transcript_variant	5/7	3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

243068

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

131526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000315

Gnomad ASJ exome

AF:

0.000511

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1456022

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

724298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000701

Gnomad4 ASJ exome

AF:

0.000539

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.000141

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2024

The c.487T>A (p.C163S) alteration is located in exon 5 (coding exon 4) of the MS4A3 gene. This alteration results from a T to A substitution at nucleotide position 487, causing the cysteine (C) at amino acid position 163 to be replaced by a serine (S). 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

Pathogenic

0.82

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.13

.;.;T;.

Eigen

Benign

0.068

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.49

T;T;.;.

M_CAP

Benign

0.0045

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.6

.;.;H;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-7.3

D;D;D;D

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D

Vest4

0.69

MutPred

0.77

.;.;Gain of disorder (P = 3e-04);.;

MVP

0.055

MPC

0.11

ClinPred

0.68

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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