Genetic Variant ENST00000524868.1:c.-440T>C (chr11-60088238-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000524868.1(MS4A2):c.-440T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 161,544 control chromosomes in the GnomAD database, including 847 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.073 ( 843 hom., cov: 32)

Exomes 𝑓: 0.024 ( 4 hom. )

Consequence

MS4A2
ENST00000524868.1 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.04

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

IgE responsiveness, atopic
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

MS4A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein	UniProt
MS4A2	XM_005273846.5 link	c.-419T>C	upstream_gene_variant	XP_005273903.1
MS4A2	XM_011544850.3 link	c.-103T>C	upstream_gene_variant	XP_011543152.1	Q01362
MS4A2	XM_017017362.2 link	c.-419T>C	upstream_gene_variant	XP_016872851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MS4A2	ENST00000524868.1 link	c.-440T>C		upstream_gene_variant		4		ENSP00000433311.1		E9PLJ1

Frequencies

GnomAD3 genomes

AF:

0.0733

AC:

11144

AN:

152118

Hom.:

841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0349

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.0489

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0216

Gnomad OTH

AF:

0.0636

GnomAD4 exome

AF:

0.0244

AC:

227

AN:

9308

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

136

AN XY:

4920

show subpopulations

African (AFR)

AF:

0.205

AC:

AN:

American (AMR)

AF:

0.0249

AC:

AN:

1448

Ashkenazi Jewish (ASJ)

AF:

0.0745

AC:

AN:

East Asian (EAS)

AF:

0.101

AC:

AN:

318

South Asian (SAS)

AF:

0.0444

AC:

AN:

810

European-Finnish (FIN)

AF:

0.00505

AC:

AN:

198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0166

AC:

AN:

5976

Other (OTH)

AF:

0.0172

AC:

AN:

408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0733

AC:

11155

AN:

152236

Hom.:

843

Cov.:

AF XY:

0.0713

AC XY:

5310

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.183

AC:

7594

AN:

41516

American (AMR)

AF:

0.0348

AC:

533

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3470

East Asian (EAS)

AF:

0.170

AC:

884

AN:

5188

South Asian (SAS)

AF:

0.0485

AC:

234

AN:

4826

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0216

AC:

1467

AN:

68016

Other (OTH)

AF:

0.0620

AC:

131

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

488

976

1465

1953

2441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0404

Hom.:

1147

Bravo

AF:

0.0808

Asia WGS

AF:

0.117

AC:

407

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.59

(source)

DANN

Benign

0.68

PhyloP100

-1.0

PromoterAI

0.0088

Neutral

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over