rs2297020

chr6-46835281-A-T

Variant summary

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

The NM_005588.3(MEP1A):c.1816A>T(p.Thr606Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,600,788 control chromosomes in the GnomAD database, including 54,302 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.29 (7051 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47251 hom.)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.784

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5639277E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEP1A	NM_005588.3	c.1816A>T	p.Thr606Ser	missense_variant	13/14	ENST00000230588.9
MEP1A	XM_011514628.2	c.1900A>T	p.Thr634Ser	missense_variant	12/13
MEP1A	XM_011514629.3	c.1816A>T	p.Thr606Ser	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEP1A	ENST00000230588.9	c.1816A>T	p.Thr606Ser	missense_variant	13/14	1	NM_005588.3	P1
MEP1A	ENST00000611727.2	c.1900A>T	p.Thr634Ser	missense_variant	12/13	1
MEP1A	ENST00000680769.1	n.1997A>T		non_coding_transcript_exon_variant	11/12
MEP1A	ENST00000680229.1	c.*1001A>T		3_prime_UTR_variant, NMD_transcript_variant	13/14

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44468 AN: 151900 Hom.: 7037 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.272 AC: 62670 AN: 230770 Hom.: 8724 AF XY: 0.268 AC XY: 33323 AN XY: 124404

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.289

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.252 AC: 365050 AN: 1448770 Hom.: 47251 Cov.: 34 AF XY: 0.252 AC XY: 181568 AN XY: 719504

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.293 AC: 44530 AN: 152018 Hom.: 7051 Cov.: 32 AF XY: 0.290 AC XY: 21583 AN XY: 74312

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.277

Alfa AF: 0.255 Hom.: 1703

Bravo AF: 0.303

TwinsUK AF: 0.248 AC: 921

ALSPAC AF: 0.240 AC: 924

ESP6500AA AF: 0.392 AC: 1728

ESP6500EA AF: 0.247 AC: 2119

ExAC AF: 0.265 AC: 32099

Asia WGS AF: 0.293 AC: 1017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.74
Dann	Benign	0.71
DEOGEN2	Benign	0.085	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.00046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.063
Sift	Benign	0.097	T;.
Sift4G	Benign	0.086	T;T
Polyphen		0.025	B;B
Vest4		0.14
MutPred		0.064		Loss of glycosylation at T606 (P = 0.0421);.;
MPC		0.098
ClinPred		0.019	T
GERP RS		-10
Varity_R		0.047
gMVP		0.19

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: rs2297020; hg19: chr6-46803018; COSMIC: COSV57919761;