6-46826456-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005588.3(MEP1A):c.881G>A(p.Ser294Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16654998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEP1A	NM_005588.3	c.881G>A	p.Ser294Asn	missense_variant	9/14	ENST00000230588.9
MEP1A	XM_011514628.2	c.965G>A	p.Ser322Asn	missense_variant	8/13
MEP1A	XM_011514629.3	c.881G>A	p.Ser294Asn	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEP1A	ENST00000230588.9	c.881G>A	p.Ser294Asn	missense_variant	9/14	1	NM_005588.3	P1
MEP1A	ENST00000611727.2	c.965G>A	p.Ser322Asn	missense_variant	8/13	1
MEP1A	ENST00000680769.1	n.1062G>A		non_coding_transcript_exon_variant	7/12
MEP1A	ENST00000680229.1	c.*66G>A		3_prime_UTR_variant, NMD_transcript_variant	9/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 05, 2024

The c.881G>A (p.S294N) 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 881, causing the serine (S) at amino acid position 294 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	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	-0.055
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.81	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.91	N;.
REVEL	Benign	0.12
Sift	Benign	0.20	T;.
Sift4G	Benign	0.41	T;T
Polyphen		0.039	B;B
Vest4		0.20
MutPred		0.57		Gain of relative solvent accessibility (P = 0.0479);.;
MVP		0.44
MPC		0.14
ClinPred		0.56	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.24

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: chr6-46794193;