11-60335034-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139249.4(MS4A6E):c.139G>T(p.Val47Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,613,452 control chromosomes in the GnomAD database, including 89,900 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (8395 hom., cov: 31)
  • Exomes 𝑓: 0.33 (81505 hom.)
• Consequence: MS4A6E NM_139249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164

Genes affected

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3646483E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MS4A6E	NM_139249.4	c.139G>T	p.Val47Phe	missense_variant	2/5	ENST00000684409.1
MS4A6E	NR_170614.1	n.307G>T		non_coding_transcript_exon_variant	2/6
MS4A6E	NR_170615.1	n.307G>T		non_coding_transcript_exon_variant	2/5
MS4A6E	NR_170616.1	n.307G>T		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MS4A6E	ENST00000684409.1	c.139G>T	p.Val47Phe	missense_variant	2/5		NM_139249.4	P1
MS4A6E	ENST00000300182.8	c.139G>T	p.Val47Phe	missense_variant	1/4	1		P1
MS4A6E	ENST00000532756.1	c.64G>T	p.Val22Phe	missense_variant, NMD_transcript_variant	1/5	4
MS4A6E	ENST00000530509.1	c.58G>T	p.Val20Phe	missense_variant, NMD_transcript_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48458 AN: 151798 Hom.: 8373 Cov.: 31

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.292

GnomAD3 exomes AF: 0.324 AC: 81431 AN: 251242 Hom.: 14775 AF XY: 0.315 AC XY: 42737 AN XY: 135794

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.269

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.327 AC: 477543 AN: 1461536 Hom.: 81505 Cov.: 38 AF XY: 0.321 AC XY: 233442 AN XY: 727070

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.303

GnomAD4 genome AF: 0.319 AC: 48523 AN: 151916 Hom.: 8395 Cov.: 31 AF XY: 0.327 AC XY: 24295 AN XY: 74238

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.264

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.295

Alfa AF: 0.310 Hom.: 18716

Bravo AF: 0.304

TwinsUK AF: 0.345 AC: 1281

ALSPAC AF: 0.330 AC: 1273

ESP6500AA AF: 0.258 AC: 1137

ESP6500EA AF: 0.336 AC: 2890

ExAC AF: 0.318 AC: 38662

Asia WGS AF: 0.223 AC: 776 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	8.4
Dann	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.044
Sift	Benign	0.044	D
Sift4G	Benign	0.098	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.039
ClinPred		0.035	T
GERP RS		2.2
Varity_R		0.14
gMVP		0.54

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: rs2304933; hg19: chr11-60102507; COSMIC: COSV55728153;