chr11-60462439-C-A

Variant names:

• chr11-60462439-C-A
• rs2135197243
• NM_152866.3:c.65C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152866.3(MS4A1):​c.65C>A​(p.Ala22Asp) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MS4A1 NM_152866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0180
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07355216).

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.65C>A	p.Ala22Asp	missense	Exon 3 of 8	NP_690605.1	P11836-1
	MS4A1	NM_021950.4		c.65C>A	p.Ala22Asp	missense	Exon 2 of 7	NP_068769.2
	MS4A1	NM_152867.2		c.65C>A	p.Ala22Asp	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.65C>A	p.Ala22Asp	missense	Exon 3 of 8	ENSP00000314620.7	P11836-1
	MS4A1	ENST00000389939.2	TSL:1	c.65C>A	p.Ala22Asp	missense	Exon 1 of 6	ENSP00000374589.2	P11836-1
	MS4A1	ENST00000532073.5	TSL:1	c.65C>A	p.Ala22Asp	missense	Exon 2 of 7	ENSP00000433519.1	E9PKH8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.81
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.018
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.0080
Sift	Benign	0.091	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0060	B
Vest4		0.23
MutPred		0.26		Loss of MoRF binding (P = 0.0635)
MVP		0.27
MPC		0.048
ClinPred		0.096	T
GERP RS		-0.26
PromoterAI		-0.013	Neutral
Varity_R		0.13
gMVP		0.56
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2135197243; hg19: chr11-60229912;