chr6-46833334-G-T

Variant names:

• chr6-46833334-G-T
• rs2274658
• NM_005588.3:c.1405G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005588.3(MEP1A):​c.1405G>T​(p.Val469Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,613,798 control chromosomes in the GnomAD database, including 128,185 homozygotes. 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: 𝑓 0.42 (13963 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114222 hom.)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.614
• Publications: 25 publications found

Genes affected

MEP1A (HGNC:7015): (meprin A subunit alpha) Predicted to enable metalloendopeptidase activity. Predicted to be involved in proteolysis. Located in extracellular exosome. Part of meprin A complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.346789E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEP1A	NM_005588.3	c.1405G>T	p.Val469Leu	missense_variant	Exon 11 of 14	ENST00000230588.9	NP_005579.2
MEP1A	XM_011514628.2	c.1489G>T	p.Val497Leu	missense_variant	Exon 10 of 13		XP_011512930.1
MEP1A	XM_011514629.3	c.1405G>T	p.Val469Leu	missense_variant	Exon 11 of 14		XP_011512931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEP1A	ENST00000230588.9	c.1405G>T	p.Val469Leu	missense_variant	Exon 11 of 14	1	NM_005588.3	ENSP00000230588.4

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64242 AN: 151924 Hom.: 13946 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.415

GnomAD2 exomes AF: 0.395 AC: 99288 AN: 251458 AF XY: 0.392

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.452

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.392

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.392 AC: 572900 AN: 1461756 Hom.: 114222 Cov.: 45 AF XY: 0.392 AC XY: 285410 AN XY: 727182

African (AFR) AF: 0.511 AC: 17113 AN: 33480

American (AMR) AF: 0.453 AC: 20259 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10635 AN: 26136

East Asian (EAS) AF: 0.193 AC: 7650 AN: 39696

South Asian (SAS) AF: 0.404 AC: 34869 AN: 86258

European-Finnish (FIN) AF: 0.389 AC: 20764 AN: 53416

Middle Eastern (MID) AF: 0.453 AC: 2614 AN: 5768

European-Non Finnish (NFE) AF: 0.391 AC: 434737 AN: 1111886

Other (OTH) AF: 0.402 AC: 24259 AN: 60392

GnomAD4 genome AF: 0.423 AC: 64307 AN: 152042 Hom.: 13963 Cov.: 32 AF XY: 0.421 AC XY: 31295 AN XY: 74308

African (AFR) AF: 0.499 AC: 20664 AN: 41446

American (AMR) AF: 0.435 AC: 6641 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1351 AN: 3470

East Asian (EAS) AF: 0.189 AC: 982 AN: 5188

South Asian (SAS) AF: 0.407 AC: 1962 AN: 4820

European-Finnish (FIN) AF: 0.382 AC: 4037 AN: 10564

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27174 AN: 67960

Other (OTH) AF: 0.417 AC: 879 AN: 2108

Alfa AF: 0.403 Hom.: 24704

Bravo AF: 0.431

TwinsUK AF: 0.391 AC: 1451

ALSPAC AF: 0.394 AC: 1519

ESP6500AA AF: 0.505 AC: 2227

ESP6500EA AF: 0.397 AC: 3416

ExAC AF: 0.394 AC: 47851

Asia WGS AF: 0.367 AC: 1278 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.66
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.000033	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.59	N;.
PhyloP100		0.61
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.027
Sift	Benign	0.32	T;.
Sift4G	Benign	0.40	T;T
Vest4		0.026
ClinPred		0.0021	T
GERP RS		1.2
Varity_R		0.064
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2274658; hg19: chr6-46801071; COSMIC: COSV57918913;