11-60094001-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000139.5(MS4A2):​c.575G>A​(p.Gly192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MS4A2
NM_000139.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.267
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]

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ACMG classification

Classification made for transcript

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=0.20384908).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MS4A2NM_000139.5 linkc.575G>A p.Gly192Glu missense_variant Exon 6 of 7 ENST00000278888.8 NP_000130.1 Q01362

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MS4A2ENST00000278888.8 linkc.575G>A p.Gly192Glu missense_variant Exon 6 of 7 1 NM_000139.5 ENSP00000278888.3 Q01362
MS4A2ENST00000617306.1 linkc.440G>A p.Gly147Glu missense_variant Exon 5 of 6 1 ENSP00000482594.1 A0A0B4J2E9
MS4A2ENST00000440896.2 linkn.1082G>A non_coding_transcript_exon_variant Exon 5 of 5 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461800
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.575G>A (p.G192E) alteration is located in exon 6 (coding exon 6) of the MS4A2 gene. This alteration results from a G to A substitution at nucleotide position 575, causing the glycine (G) at amino acid position 192 to be replaced by a glutamic acid (E). 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
Uncertain
0.42
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
12
DANN
Benign
0.39
DEOGEN2
Benign
0.036
T;.
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.43
N
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.14
N;.
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.75
N;.
REVEL
Benign
0.12
Sift
Benign
1.0
T;.
Sift4G
Benign
0.38
T;D
Polyphen
0.88
P;.
Vest4
0.32
MutPred
0.63
Loss of catalytic residue at L193 (P = 0.1002);.;
MVP
0.51
MPC
0.043
ClinPred
0.16
T
GERP RS
1.3
Varity_R
0.12
gMVP
0.35

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747988240; hg19: chr11-59861474; COSMIC: COSV54012046; COSMIC: COSV54012046; API