Variant 6-46809532-T-G 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.375T>G(p.Phe125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MEP1A
NM_005588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.253

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:

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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=0.08184296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEP1A	NM_005588.3 link	c.375T>G	p.Phe125Leu	missense_variant	6/14	ENST00000230588.9	NP_005579.2	Q16819
MEP1A	XM_011514628.2 link	c.459T>G	p.Phe153Leu	missense_variant	5/13		XP_011512930.1	B7ZL91
MEP1A	XM_011514629.3 link	c.375T>G	p.Phe125Leu	missense_variant	6/14		XP_011512931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MEP1A	ENST00000230588.9 link	c.375T>G	p.Phe125Leu	missense_variant	6/14	1	NM_005588.3	ENSP00000230588.4	Q16819
MEP1A	ENST00000611727.2 link	c.459T>G	p.Phe153Leu	missense_variant	5/13	1		ENSP00000480465.1	B7ZL91
MEP1A	ENST00000680229.1 link	n.375T>G		non_coding_transcript_exon_variant	6/14			ENSP00000505289.1	A0A7P0Z478
MEP1A	ENST00000680769.1 link	n.556T>G		non_coding_transcript_exon_variant	4/12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000231

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Sep 24, 2024

The c.375T>G (p.F125L) alteration is located in exon 6 (coding exon 6) of the MEP1A gene. This alteration results from a T to G substitution at nucleotide position 375, causing the phenylalanine (F) at amino acid position 125 to be replaced by a leucine (L). 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.79

N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.69

N;.

REVEL

Benign

0.12

Sift

Benign

0.33

T;.

Sift4G

Benign

0.69

T;T

Polyphen

0.0020

B;B

Vest4

0.35

MutPred

0.55

Loss of sheet (P = 0.0817);.;

MVP

0.59

MPC

0.13

ClinPred

0.18

GERP RS

5.8

Varity_R

0.057

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over