11-60088812-A-C

Variant names:

• chr11-60088812-A-C
• rs1855699366
• NM_000139.5:c.47A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000139.5(MS4A2):​c.47A>C​(p.Glu16Ala) 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. 14/21 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)
• Consequence: MS4A2 NM_000139.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09562817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MS4A2	NM_000139.5	c.47A>C	p.Glu16Ala	missense_variant	Exon 1 of 7	ENST00000278888.8	NP_000130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MS4A2	ENST00000278888.8	c.47A>C	p.Glu16Ala	missense_variant	Exon 1 of 7	1	NM_000139.5	ENSP00000278888.3
MS4A2	ENST00000617306.1	c.47A>C	p.Glu16Ala	missense_variant	Exon 1 of 6	1		ENSP00000482594.1
MS4A2	ENST00000440896.2	n.149A>C		non_coding_transcript_exon_variant	Exon 1 of 5	1
MS4A2	ENST00000524868.1	c.47A>C	p.Glu16Ala	missense_variant	Exon 2 of 3	4		ENSP00000433311.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47A>C (p.E16A) alteration is located in exon 1 (coding exon 1) of the MS4A2 gene. This alteration results from a A to C substitution at nucleotide position 47, causing the glutamic acid (E) at amino acid position 16 to be replaced by an alanine (A). 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	Benign	0.10
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.065
DANN	Benign	0.57
DEOGEN2	Benign	0.088	.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.8	D;N;.
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;T;.
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.30	.;B;.
Vest4		0.16, 0.14
MVP		0.50
MPC		0.021
ClinPred		0.96	D
GERP RS		-8.8
Varity_R		0.038
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs1855699366; hg19: chr11-59856285;