11-60462421-C-T

Variant summary

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

The NM_152866.3(MS4A1):​c.47C>T​(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 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 (★). Synonymous variant affecting the same amino acid position (i.e. P16P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MS4A1
NM_152866.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.44
Variant links:
Genes affected
MS4A1 (HGNC:7315): (membrane spanning 4-domains A1) This gene encodes 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 gene encodes a B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants which encode the same protein. [provided by RefSeq, Jul 2008]

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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=0.100269526).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MS4A1NM_152866.3 linkc.47C>T p.Pro16Leu missense_variant Exon 3 of 8 ENST00000345732.9 NP_690605.1 P11836-1A0A024R507
MS4A1NM_021950.4 linkc.47C>T p.Pro16Leu missense_variant Exon 2 of 7 NP_068769.2 P11836-1A0A024R507
MS4A1NM_152867.2 linkc.47C>T p.Pro16Leu missense_variant Exon 2 of 7 NP_690606.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MS4A1ENST00000345732.9 linkc.47C>T p.Pro16Leu missense_variant Exon 3 of 8 1 NM_152866.3 ENSP00000314620.7 P11836-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Sep 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 16 of the MS4A1 protein (p.Pro16Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MS4A1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;T;D;.;T;D
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.22
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.81
.;T;.;T;T;T
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.098
T;T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.2
M;.;M;M;.;M
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-3.1
D;D;D;D;D;D
REVEL
Benign
0.10
Sift
Benign
0.13
T;D;T;D;D;T
Sift4G
Uncertain
0.017
D;D;D;D;D;D
Polyphen
0.48
P;P;P;.;.;P
Vest4
0.42
MutPred
0.30
Loss of ubiquitination at K18 (P = 0.0447);Loss of ubiquitination at K18 (P = 0.0447);Loss of ubiquitination at K18 (P = 0.0447);Loss of ubiquitination at K18 (P = 0.0447);.;Loss of ubiquitination at K18 (P = 0.0447);
MVP
0.59
MPC
0.055
ClinPred
0.75
D
GERP RS
5.2
Varity_R
0.094
gMVP
0.39

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: rs768892705; hg19: chr11-60229894; COSMIC: COSV105243667; COSMIC: COSV105243667; API