chr11-60302703-A-G

Position:

• chr11-60302703-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148975.3(MS4A4A):​c.532A>G​(p.Met178Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,611,886 control chromosomes in the GnomAD database, including 71,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (6797 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64570 hom.)
• Consequence: MS4A4A NM_148975.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.37

Genes affected

MS4A4A (HGNC:13371): (membrane spanning 4-domains A4A) This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features, similar intron/exon splice boundaries, and display unique expression patterns in hematopoietic cells and nonlymphoid tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00714615).
• BP6: Variant 11-60302703-A-G is Benign according to our data. Variant chr11-60302703-A-G is described in ClinVar as [Benign]. Clinvar id is 1223746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MS4A4A	NM_148975.3	c.532A>G	p.Met178Val	missense_variant	5/7	ENST00000337908.5
MS4A4A	NM_024021.4	c.475A>G	p.Met159Val	missense_variant	6/8
MS4A4A	NM_001243266.2	c.387+1646A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MS4A4A	ENST00000337908.5	c.532A>G	p.Met178Val	missense_variant	5/7	1	NM_148975.3	A2

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44800 AN: 152026 Hom.: 6797 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.305

GnomAD3 exomes AF: 0.293 AC: 73589 AN: 251238 Hom.: 11300 AF XY: 0.297 AC XY: 40344 AN XY: 135784

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.219

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.376

Gnomad SAS exome AF: 0.354

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.294 AC: 429816 AN: 1459742 Hom.: 64570 Cov.: 34 AF XY: 0.297 AC XY: 215385 AN XY: 726278

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.377

Gnomad4 EAS exome AF: 0.370

Gnomad4 SAS exome AF: 0.352

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.295 AC: 44816 AN: 152144 Hom.: 6797 Cov.: 32 AF XY: 0.290 AC XY: 21592 AN XY: 74388

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.304

Alfa AF: 0.301 Hom.: 17236

Bravo AF: 0.296

TwinsUK AF: 0.281 AC: 1043

ALSPAC AF: 0.287 AC: 1107

ESP6500AA AF: 0.315 AC: 1386

ESP6500EA AF: 0.290 AC: 2497

ExAC AF: 0.296 AC: 35945

Asia WGS AF: 0.357 AC: 1242 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 31413141) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0010
DANN	Benign	0.12
DEOGEN2	Benign	0.00076	.;T
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.88	.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.23	.;N
REVEL	Benign	0.0060
Sift	Benign	0.84	.;T
Sift4G	Benign	0.63	.;T
Polyphen		0.0	.;B
Vest4		0.019
MPC		0.077
ClinPred		0.00041	T
GERP RS		-5.8
Varity_R		0.033
gMVP		0.078

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

Publications

LitVar

Other links and lift over

dbSNP: rs6591561; hg19: chr11-60070176; COSMIC: COSV59701295; COSMIC: COSV59701295;