chr6-46835281-A-T

Variant names:

• chr6-46835281-A-T
• rs2297020
• NM_005588.3:c.1816A>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.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. 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 0.29 (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
• Publications: 17 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=4.5639277E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 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.1816A>T	p.Thr606Ser	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.1816A>T	p.Thr606Ser	missense	Exon 13 of 14	ENSP00000230588.4	Q16819
	MEP1A	ENST00000611727.2	TSL:1	c.1900A>T	p.Thr634Ser	missense	Exon 12 of 13	ENSP00000480465.1	B7ZL91
	MEP1A	ENST00000879644.1		c.1885A>T	p.Thr629Ser	missense	Exon 14 of 15	ENSP00000549703.1

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

GnomAD2 exomes AF: 0.272 AC: 62670 AN: 230770 AF XY: 0.268

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 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

African (AFR) AF: 0.409 AC: 13580 AN: 33166

American (AMR) AF: 0.313 AC: 13414 AN: 42824

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7659 AN: 25820

East Asian (EAS) AF: 0.294 AC: 11598 AN: 39480

South Asian (SAS) AF: 0.309 AC: 26043 AN: 84154

European-Finnish (FIN) AF: 0.202 AC: 10650 AN: 52840

Middle Eastern (MID) AF: 0.254 AC: 1198 AN: 4716

European-Non Finnish (NFE) AF: 0.240 AC: 265240 AN: 1105920

Other (OTH) AF: 0.262 AC: 15668 AN: 59850

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

African (AFR) AF: 0.407 AC: 16857 AN: 41432

American (AMR) AF: 0.307 AC: 4691 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1046 AN: 3472

East Asian (EAS) AF: 0.283 AC: 1458 AN: 5158

South Asian (SAS) AF: 0.321 AC: 1548 AN: 4822

European-Finnish (FIN) AF: 0.194 AC: 2051 AN: 10580

Middle Eastern (MID) AF: 0.231 AC: 67 AN: 290

European-Non Finnish (NFE) AF: 0.237 AC: 16083 AN: 67970

Other (OTH) AF: 0.277 AC: 585 AN: 2112

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 v4.9

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
MetaRNN	Benign	0.00046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.78
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.063
Sift	Benign	0.097	T
Sift4G	Benign	0.086	T
Polyphen		0.025	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
Mutation Taster		=99/1	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: rs2297020; hg19: chr6-46803018; COSMIC: COSV57919761;