6-46826437-G-A

Position:

• chr6-46826437-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005588.3(MEP1A):​c.862G>A​(p.Asp288Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEP1A	NM_005588.3	c.862G>A	p.Asp288Asn	missense_variant	9/14	ENST00000230588.9
MEP1A	XM_011514628.2	c.946G>A	p.Asp316Asn	missense_variant	8/13
MEP1A	XM_011514629.3	c.862G>A	p.Asp288Asn	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEP1A	ENST00000230588.9	c.862G>A	p.Asp288Asn	missense_variant	9/14	1	NM_005588.3	P1
MEP1A	ENST00000611727.2	c.946G>A	p.Asp316Asn	missense_variant	8/13	1
MEP1A	ENST00000680769.1	n.1043G>A		non_coding_transcript_exon_variant	7/12
MEP1A	ENST00000680229.1	c.*47G>A		3_prime_UTR_variant, NMD_transcript_variant	9/14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.862G>A (p.D288N) alteration is located in exon 9 (coding exon 9) of the MEP1A gene. This alteration results from a G to A substitution at nucleotide position 862, causing the aspartic acid (D) at amino acid position 288 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	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Benign	0.29
Sift	Benign	0.035	D;.
Sift4G	Uncertain	0.023	D;D
Polyphen		0.98	D;D
Vest4		0.22
MutPred		0.60		Loss of catalytic residue at D288 (P = 0.0784);.;
MVP		0.47
MPC		0.24
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.36
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-46794174;