11-60389568-A-T

Position:

• chr11-60389568-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021201.5(MS4A7):​c.518A>T​(p.Asp173Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MS4A7 NM_021201.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

Genes affected

MS4A7 (HGNC:13378): (membrane spanning 4-domains A7) This gene encodes a member of the membrane-spanning 4A gene family, members of which are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns in hematopoietic cells and nonlymphoid tissues. This family member is associated with mature cellular function in the monocytic lineage, and it may be a component of a receptor complex involved in signal transduction. This gene is localized to 11q12, in a cluster of other family members. At least four alternatively spliced transcript variants encoding two distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MS4A14 (HGNC:30706): (membrane spanning 4-domains A14) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MS4A6E (HGNC:14285): (membrane spanning 4-domains A6E) 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. The gene encoding this protein is localized to 11q12.3, among a cluster of family members. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MS4A7	NM_021201.5	c.518A>T	p.Asp173Val	missense_variant	5/7	ENST00000300184.8
MS4A7	NM_206939.2	c.518A>T	p.Asp173Val	missense_variant	5/7
MS4A7	NM_206938.2	c.383A>T	p.Asp128Val	missense_variant	4/6
MS4A7	NM_206940.2	c.383A>T	p.Asp128Val	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MS4A7	ENST00000300184.8	c.518A>T	p.Asp173Val	missense_variant	5/7	1	NM_021201.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.518A>T (p.D173V) alteration is located in exon 5 (coding exon 4) of the MS4A7 gene. This alteration results from a A to T substitution at nucleotide position 518, causing the aspartic acid (D) at amino acid position 173 to be replaced by a valine (V). 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	Benign	0.18
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T;.;.;.;.
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.78	T;T;.;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.98	D;P;P;P;.
Vest4		0.59
MutPred		0.66		Gain of helix (P = 0.0199);.;.;.;.;
MVP		0.30
MPC		0.21
ClinPred		0.87	D
GERP RS		3.7
Varity_R		0.46
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-60157041;