6-46825438-G-C

Variant names:

• chr6-46825438-G-C
• rs6920863
• NM_005588.3:c.723G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005588.3(MEP1A):​c.723G>C​(p.Gln241His) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEP1A NM_005588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 14 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEP1A	NM_005588.3	c.723G>C	p.Gln241His	missense_variant	Exon 8 of 14	ENST00000230588.9	NP_005579.2
MEP1A	XM_011514628.2	c.807G>C	p.Gln269His	missense_variant	Exon 7 of 13		XP_011512930.1
MEP1A	XM_011514629.3	c.723G>C	p.Gln241His	missense_variant	Exon 8 of 14		XP_011512931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEP1A	ENST00000230588.9	c.723G>C	p.Gln241His	missense_variant	Exon 8 of 14	1	NM_005588.3	ENSP00000230588.4
MEP1A	ENST00000611727.2	c.807G>C	p.Gln269His	missense_variant	Exon 7 of 13	1		ENSP00000480465.1
MEP1A	ENST00000680229.1	n.723G>C		non_coding_transcript_exon_variant	Exon 8 of 14			ENSP00000505289.1
MEP1A	ENST00000680769.1	n.904G>C		non_coding_transcript_exon_variant	Exon 6 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 14049

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.0096	D
MutationAssessor	Pathogenic	3.7	H;.
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.87
ClinPred		0.99	D
GERP RS		0.70
Varity_R		0.73
gMVP		0.79
Mutation Taster		=80/20	polymorphism

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: rs6920863; hg19: chr6-46793175;