11-60094059-C-A

Position:

chr11-60094059-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000139.5(MS4A2):c.633C>A(p.Asn211Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,606,552 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0083 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 26 hom. )

Consequence

MS4A2
NM_000139.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.98

Variant links:

Genes affected

MS4A2 (HGNC:7316): (membrane spanning 4-domains A2) The allergic response involves the binding of allergen to receptor-bound IgE followed by cell activation and the release of mediators responsible for the manifestations of allergy. The IgE-receptor, a tetramer composed of an alpha, beta, and 2 disulfide-linked gamma chains, is found on the surface of mast cells and basophils. This gene encodes the beta subunit of the high affinity IgE receptor which is 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 family member is localized to 11q12, among a cluster of membrane-spanning 4A gene family members. Alternative splicing results in multiple transcript variants encoding distinct proteins. Additional transcript variants have been described but require experimental validation. [provided by RefSeq, Mar 2012]

MS4A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047402084).

BP6

Variant 11-60094059-C-A is Benign according to our data. Variant chr11-60094059-C-A is described in ClinVar as [Benign]. Clinvar id is 790092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00831 (1264/152194) while in subpopulation AFR AF= 0.0279 (1160/41524). AF 95% confidence interval is 0.0266. There are 12 homozygotes in gnomad4. There are 638 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MS4A2	NM_000139.5 linkuse as main transcript	c.633C>A	p.Asn211Lys	missense_variant	6/7	ENST00000278888.8	NP_000130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MS4A2	ENST00000278888.8 linkuse as main transcript	c.633C>A	p.Asn211Lys	missense_variant	6/7	1	NM_000139.5	ENSP00000278888	P1
MS4A2	ENST00000617306.1 linkuse as main transcript	c.498C>A	p.Asn166Lys	missense_variant	5/6	1		ENSP00000482594
MS4A2	ENST00000440896.2 linkuse as main transcript			downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1263

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00244

AC:

613

AN:

251346

Hom.:

AF XY:

0.00189

AC XY:

257

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0303

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00107

AC:

1551

AN:

1454358

Hom.:

Cov.:

AF XY:

0.000975

AC XY:

706

AN XY:

724054

show subpopulations

Gnomad4 AFR exome

AF:

0.0300

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000252

Gnomad4 OTH exome

AF:

0.00254

GnomAD4 genome

AF:

0.00831

AC:

1264

AN:

152194

Hom.:

Cov.:

AF XY:

0.00857

AC XY:

638

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0279

Gnomad4 AMR

AF:

0.00478

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00905

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00301

AC:

366

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.0010

DANN

Benign

0.20

DEOGEN2

Benign

0.083

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0057

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.058

Sift

Benign

0.53

T;.

Sift4G

Benign

0.59

T;T

Polyphen

0.0

B;.

Vest4

0.061

MutPred

0.18

Gain of solvent accessibility (P = 0.0058);.;

MVP

0.25

MPC

0.021

ClinPred

0.0025

GERP RS

-4.8

Varity_R

0.027

gMVP

0.15

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