dbSNP rs12197930: MEP1A:p.Arg476Gly (chr6-46833355-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005588.3(MEP1A):c.1426A>G(p.Arg476Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,614,164 control chromosomes in the GnomAD database, including 1,300 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.045 ( 164 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1136 hom. )

Consequence

MEP1A
NM_005588.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.622

Publications

12 publications found

Variant links:

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]

MEP1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0025639832).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEP1A	NM_005588.3 link	c.1426A>G	p.Arg476Gly	missense_variant	Exon 11 of 14	ENST00000230588.9	NP_005579.2	Q16819
MEP1A	XM_011514628.2 link	c.1510A>G	p.Arg504Gly	missense_variant	Exon 10 of 13		XP_011512930.1	B7ZL91
MEP1A	XM_011514629.3 link	c.1426A>G	p.Arg476Gly	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 link	c.1426A>G	p.Arg476Gly	missense_variant	Exon 11 of 14	1	NM_005588.3	ENSP00000230588.4		Q16819

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6896

AN:

152224

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0712

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0387

Gnomad ASJ

AF:

0.0599

Gnomad EAS

AF:

0.0136

Gnomad SAS

AF:

0.0612

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0492

GnomAD2 exomes

AF:

0.0420

AC:

10569

AN:

251478

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.0747

Gnomad AMR exome

AF:

0.0412

Gnomad ASJ exome

AF:

0.0697

Gnomad EAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.0296

Gnomad NFE exome

AF:

0.0344

Gnomad OTH exome

AF:

0.0401

GnomAD4 exome

AF:

0.0352

AC:

51456

AN:

1461822

Hom.:

1136

Cov.:

AF XY:

0.0366

AC XY:

26600

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0698

AC:

2338

AN:

33478

American (AMR)

AF:

0.0405

AC:

1810

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0712

AC:

1861

AN:

26134

East Asian (EAS)

AF:

0.0126

AC:

499

AN:

39700

South Asian (SAS)

AF:

0.0682

AC:

5882

AN:

86256

European-Finnish (FIN)

AF:

0.0291

AC:

1556

AN:

53416

Middle Eastern (MID)

AF:

0.0817

AC:

471

AN:

5768

European-Non Finnish (NFE)

AF:

0.0311

AC:

34607

AN:

1111952

Other (OTH)

AF:

0.0403

AC:

2432

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2888

5776

8663

11551

14439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0452

AC:

6891

AN:

152342

Hom.:

164

Cov.:

AF XY:

0.0440

AC XY:

3279

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0710

AC:

2952

AN:

41568

American (AMR)

AF:

0.0385

AC:

590

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

208

AN:

3472

East Asian (EAS)

AF:

0.0137

AC:

AN:

5190

South Asian (SAS)

AF:

0.0609

AC:

294

AN:

4830

European-Finnish (FIN)

AF:

0.0276

AC:

293

AN:

10624

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0342

AC:

2325

AN:

68028

Other (OTH)

AF:

0.0482

AC:

102

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

346

692

1039

1385

1731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0391

Hom.:

208

Bravo

AF:

0.0473

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.0744

AC:

328

ESP6500EA

AF:

0.0348

AC:

299

ExAC

AF:

0.0430

AC:

5216

Asia WGS

AF:

0.0400

AC:

142

AN:

3478

EpiCase

AF:

0.0324

EpiControl

AF:

0.0356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.5

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

0.62

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.034

Sift

Benign

0.38

T;.

Sift4G

Benign

0.42

T;T

Polyphen

0.0040

B;B

Vest4

0.26

MPC

0.14

ClinPred

0.0046

GERP RS

0.12

Varity_R

0.064

gMVP

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs12197930

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over