11-60393839-G-A

Position:

• chr11-60393839-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021201.5(MS4A7):​c.701G>A​(p.Ser234Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MS4A7 NM_021201.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.265

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]

MS4A7 (HGNC:):

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034692436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MS4A7	NM_021201.5	c.701G>A	p.Ser234Asn	missense_variant	7/7	ENST00000300184.8	NP_067024.1
MS4A7	NM_206939.2	c.701G>A	p.Ser234Asn	missense_variant	7/7		NP_996822.1
MS4A7	NM_206938.2	c.566G>A	p.Ser189Asn	missense_variant	6/6		NP_996821.1
MS4A7	NM_206940.2	c.566G>A	p.Ser189Asn	missense_variant	6/6		NP_996823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MS4A7	ENST00000300184.8	c.701G>A	p.Ser234Asn	missense_variant	7/7	1	NM_021201.5	ENSP00000300184.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248136 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458758 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000679

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 12, 2024

The c.701G>A (p.S234N) alteration is located in exon 7 (coding exon 6) of the MS4A7 gene. This alteration results from a G to A substitution at nucleotide position 701, causing the serine (S) at amino acid position 234 to be replaced by an asparagine (N). 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	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.78
DEOGEN2	Benign	0.0017	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.36	T;T;.
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.040
MutPred		0.22		Gain of helix (P = 0.0034);.;.;
MVP		0.076
MPC		0.026
ClinPred		0.028	T
GERP RS		-2.4
Varity_R		0.037
gMVP		0.044

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

Publications

LitVar

Other links and lift over

dbSNP: rs746984260; hg19: chr11-60161312;