11-60462421-C-T

Variant names:

• chr11-60462421-C-T
• rs768892705
• NM_152866.3:c.47C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

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]

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=0.100269526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MS4A1	NM_152866.3	c.47C>T	p.Pro16Leu	missense_variant	Exon 3 of 8	ENST00000345732.9	NP_690605.1
MS4A1	NM_021950.4	c.47C>T	p.Pro16Leu	missense_variant	Exon 2 of 7		NP_068769.2
MS4A1	NM_152867.2	c.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
MS4A1	ENST00000345732.9	c.47C>T	p.Pro16Leu	missense_variant	Exon 3 of 8	1	NM_152866.3	ENSP00000314620.7

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

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

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

Other links and lift over

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