6-46835365-A-G

Variant names:

• chr6-46835365-A-G
• rs2297019
• NM_005588.3:c.1900A>G

Variant summary

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

The NM_005588.3(MEP1A):​c.1900A>G​(p.Met634Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,610,370 control chromosomes in the GnomAD database, including 56,640 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 0.31 (8060 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48580 hom.)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.85
• Publications: 20 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=2.2250414E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005588.3. 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
	MEP1A	NM_005588.3	MANE Select	c.1900A>G	p.Met634Val	missense	Exon 13 of 14	NP_005579.2	Q16819

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEP1A	ENST00000230588.9	TSL:1 MANE Select	c.1900A>G	p.Met634Val	missense	Exon 13 of 14	ENSP00000230588.4	Q16819
	MEP1A	ENST00000611727.2	TSL:1	c.1984A>G	p.Met662Val	missense	Exon 12 of 13	ENSP00000480465.1	B7ZL91
	MEP1A	ENST00000879644.1		c.1969A>G	p.Met657Val	missense	Exon 14 of 15	ENSP00000549703.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46818 AN: 152018 Hom.: 8041 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.277 AC: 67879 AN: 244688 AF XY: 0.272

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.242

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.254 AC: 370044 AN: 1458234 Hom.: 48580 Cov.: 37 AF XY: 0.254 AC XY: 184100 AN XY: 725060

African (AFR) AF: 0.464 AC: 15508 AN: 33412

American (AMR) AF: 0.319 AC: 14088 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7739 AN: 26044

East Asian (EAS) AF: 0.293 AC: 11607 AN: 39606

South Asian (SAS) AF: 0.307 AC: 26285 AN: 85574

European-Finnish (FIN) AF: 0.202 AC: 10743 AN: 53208

Middle Eastern (MID) AF: 0.250 AC: 1419 AN: 5666

European-Non Finnish (NFE) AF: 0.240 AC: 266711 AN: 1110300

Other (OTH) AF: 0.265 AC: 15944 AN: 60242

GnomAD4 genome AF: 0.308 AC: 46893 AN: 152136 Hom.: 8060 Cov.: 32 AF XY: 0.305 AC XY: 22691 AN XY: 74370

African (AFR) AF: 0.460 AC: 19093 AN: 41506

American (AMR) AF: 0.313 AC: 4790 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1046 AN: 3468

East Asian (EAS) AF: 0.281 AC: 1453 AN: 5168

South Asian (SAS) AF: 0.317 AC: 1523 AN: 4810

European-Finnish (FIN) AF: 0.195 AC: 2061 AN: 10596

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.237 AC: 16100 AN: 67992

Other (OTH) AF: 0.290 AC: 613 AN: 2112

Alfa AF: 0.257 Hom.: 3576

Bravo AF: 0.321

TwinsUK AF: 0.248 AC: 921

ALSPAC AF: 0.240 AC: 924

ESP6500AA AF: 0.441 AC: 1942

ESP6500EA AF: 0.250 AC: 2152

ExAC AF: 0.279 AC: 33896

Asia WGS AF: 0.292 AC: 1015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0020
DANN	Benign	0.34
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.00022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.8
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.10
ClinPred		0.00070	T
GERP RS		-6.7
Varity_R		0.022
gMVP		0.29
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: rs2297019; hg19: chr6-46803102; COSMIC: COSV57920971;