NM_023945.3:c.311C>G

Variant names:

• chr11-60432439-C-G
• rs370162997
• NM_023945.3:c.311C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_023945.3(MS4A5):​c.311C>G​(p.Ala104Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,591,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: MS4A5 NM_023945.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

Genes affected

MS4A5 (HGNC:13374): (membrane spanning 4-domains A5) 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. Though this member is not expressed in hematopoietic cells specifically, it may be involved in signal transduction like many of its related family members. The gene encoding this protein is localized to 11q12, among a cluster of family members. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.12874374).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023945.3. 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
	MS4A5	NM_023945.3	MANE Select	c.311C>G	p.Ala104Gly	missense	Exon 3 of 5	NP_076434.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MS4A5	ENST00000300190.7	TSL:1 MANE Select	c.311C>G	p.Ala104Gly	missense	Exon 3 of 5	ENSP00000300190.2	Q9H3V2
	MS4A5	ENST00000528905.1	TSL:2	c.230C>G	p.Ala77Gly	missense	Exon 3 of 4	ENSP00000433802.1	H0YDK1
	MS4A5	ENST00000528093.1	TSL:3	c.*4C>G		3_prime_UTR	Exon 3 of 4	ENSP00000432836.1	H0YD29

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 241776 AF XY: 0.00

Gnomad AFR exome AF: 0.000197

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000486 AC: 7 AN: 1439856 Hom.: 0 Cov.: 25 AF XY: 0.00000279 AC XY: 2 AN XY: 716908

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000213 AC: 7 AN: 32906

American (AMR) AF: 0.00 AC: 0 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 84828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094526

Other (OTH) AF: 0.00 AC: 0 AN: 59538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000113501), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74316

African (AFR) AF: 0.000265 AC: 11 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.079	T
Polyphen		0.041	B
Vest4		0.41
MVP		0.12
MPC		0.020
ClinPred		0.11	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.21
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs370162997; hg19: chr11-60199912;