6-46835365-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005588.3(MEP1A):c.1900A>T(p.Met634Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M634V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.85

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049357027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEP1A	NM_005588.3	c.1900A>T	p.Met634Leu	missense_variant	13/14	ENST00000230588.9
MEP1A	XM_011514628.2	c.1984A>T	p.Met662Leu	missense_variant	12/13
MEP1A	XM_011514629.3	c.1900A>T	p.Met634Leu	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEP1A	ENST00000230588.9	c.1900A>T	p.Met634Leu	missense_variant	13/14	1	NM_005588.3	P1
MEP1A	ENST00000611727.2	c.1984A>T	p.Met662Leu	missense_variant	12/13	1
MEP1A	ENST00000680769.1	n.2081A>T		non_coding_transcript_exon_variant	11/12
MEP1A	ENST00000680229.1	c.*1085A>T		3_prime_UTR_variant, NMD_transcript_variant	13/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.0020
Dann	Benign	0.31
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.23	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.0	N;.
REVEL	Benign	0.0080
Sift	Benign	0.37	T;.
Sift4G	Benign	0.84	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.16		Gain of glycosylation at K632 (P = 0.2761);.;
MVP		0.085
MPC		0.095
ClinPred		0.091	T
GERP RS		-6.7
Varity_R		0.039
gMVP		0.27

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: rs2297019; hg19: chr6-46803102;