Variant 2-27312584-GC-GCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_002437.5(MPV17):c.284_285insG(p.Phe96LeufsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MPV17
NM_002437.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 0.188

Variant links:

Genes affected

MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]

MPV17 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-27312584-G-GC is Pathogenic according to our data. Variant chr2-27312584-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290443.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=9, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MPV17	NM_002437.5 linkuse as main transcript	c.284_285insG	p.Phe96LeufsTer17	frameshift_variant	5/8	ENST00000380044.6
MPV17	XM_005264326.5 linkuse as main transcript	c.284_285insG	p.Phe96LeufsTer17	frameshift_variant	5/8
MPV17	XM_017004151.2 linkuse as main transcript	c.236_237insG	p.Phe80LeufsTer17	frameshift_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17	ENST00000380044.6 linkuse as main transcript	c.284_285insG	p.Phe96LeufsTer17	frameshift_variant	5/8	1	NM_002437.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251244

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2015	The c.284dupG variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this duplication has not been previously reported to our knowledge, itis expected to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2023	This sequence change creates a premature translational stop signal (p.Phe96Leufs*17) in the MPV17 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPV17 are known to be pathogenic (PMID: 23714749). This variant is present in population databases (rs766160589, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of mitochondrial DNA maintenance defect (PMID: 27848944, 29282788). ClinVar contains an entry for this variant (Variation ID: 290443). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 16, 2021	PVS1, PS4_moderate, PM2, PM3 -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Pathogenic:4Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift c.284dupp.Phe96LeufsTer17 variant in MPV17 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with mitochondrial DNA maintenance defect El-Hattab et al., 2018. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Phenylalanine 96, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Phe96LeufsTer17. This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPV17 are known to be pathogenic Uusimaa et al., 2014. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000290443, PMID:27848944). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000198). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Dec 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Charcot-Marie-Tooth disease, axonal, type 2EE

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over