Variant 6-46833187-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005588.3(MEP1A):c.1258T>A(p.Tyr420Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,608,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MEP1A
NM_005588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16472524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MEP1A	NM_005588.3 linkuse as main transcript	c.1258T>A	p.Tyr420Asn	missense_variant	11/14	ENST00000230588.9
MEP1A	XM_011514628.2 linkuse as main transcript	c.1342T>A	p.Tyr448Asn	missense_variant	10/13
MEP1A	XM_011514629.3 linkuse as main transcript	c.1258T>A	p.Tyr420Asn	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MEP1A	ENST00000230588.9 linkuse as main transcript	c.1258T>A	p.Tyr420Asn	missense_variant	11/14	1	NM_005588.3	P1
MEP1A	ENST00000611727.2 linkuse as main transcript	c.1342T>A	p.Tyr448Asn	missense_variant	10/13	1
MEP1A	ENST00000680769.1 linkuse as main transcript	n.1439T>A		non_coding_transcript_exon_variant	9/12
MEP1A	ENST00000680229.1 linkuse as main transcript	c.*443T>A		3_prime_UTR_variant, NMD_transcript_variant	11/14

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

247370

Hom.:

AF XY:

0.0000524

AC XY:

AN XY:

133672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000710

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1456634

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724266

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1258T>A (p.Y420N) alteration is located in exon 11 (coding exon 11) of the MEP1A gene. This alteration results from a T to A substitution at nucleotide position 1258, causing the tyrosine (Y) at amino acid position 420 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.45

Cadd

Benign

Dann

Benign

0.92

DEOGEN2

Benign

0.092

T;.

Eigen

Benign

0.043

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.91

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.26

N;.

REVEL

Benign

0.13

Sift

Benign

0.29

T;.

Sift4G

Benign

0.31

T;T

Polyphen

0.095

B;B

Vest4

0.56

MutPred

0.62

Gain of disorder (P = 0.0227);.;

MVP

0.42

MPC

0.21

ClinPred

0.081

GERP RS

5.6

Varity_R

0.15

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over