11-60462425-G-T

Variant names:

• chr11-60462425-G-T
• rs752311016
• NM_152866.3:c.51G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152866.3(MS4A1):​c.51G>T​(p.Met17Ile) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M17T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MS4A1 NM_152866.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• Publications: 2 publications found

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]

MS4A1 Gene-Disease associations (from GenCC):

• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency, common variable, 5

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047070533).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152866.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MS4A1	NM_152866.3	MANE Select	c.51G>T	p.Met17Ile	missense	Exon 3 of 8	NP_690605.1	P11836-1
	MS4A1	NM_021950.4		c.51G>T	p.Met17Ile	missense	Exon 2 of 7	NP_068769.2
	MS4A1	NM_152867.2		c.51G>T	p.Met17Ile	missense	Exon 2 of 7	NP_690606.1	P11836-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MS4A1	ENST00000345732.9	TSL:1 MANE Select	c.51G>T	p.Met17Ile	missense	Exon 3 of 8	ENSP00000314620.7	P11836-1
	MS4A1	ENST00000389939.2	TSL:1	c.51G>T	p.Met17Ile	missense	Exon 1 of 6	ENSP00000374589.2	P11836-1
	MS4A1	ENST00000532073.5	TSL:1	c.51G>T	p.Met17Ile	missense	Exon 2 of 7	ENSP00000433519.1	E9PKH8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.3
DANN	Benign	0.92
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.10
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.073
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.23		Loss of solvent accessibility (P = 0.0036)
MVP		0.18
MPC		0.039
ClinPred		0.18	T
GERP RS		2.5
PromoterAI		-0.031	Neutral
Varity_R		0.056
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs752311016; hg19: chr11-60229898;