2-27313031-C-T

Position:

chr2-27313031-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002437.5(MPV17):c.149G>A(p.Arg50Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MPV17
NM_002437.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 5.46

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 18 ACMG points.

PM1

In a chain Protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002437.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-27313032-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 2-27313031-C-T is Pathogenic according to our data. Variant chr2-27313031-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MPV17	NM_002437.5 linkuse as main transcript	c.149G>A	p.Arg50Gln	missense_variant	3/8	ENST00000380044.6	NP_002428.1
MPV17	XM_005264326.5 linkuse as main transcript	c.149G>A	p.Arg50Gln	missense_variant	3/8		XP_005264383.1
MPV17	XM_017004151.2 linkuse as main transcript	c.101G>A	p.Arg34Gln	missense_variant	3/8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6 linkuse as main transcript	c.149G>A	p.Arg50Gln	missense_variant	3/8	1	NM_002437.5	ENSP00000369383	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251478

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135912

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the MPV17 protein (p.Arg50Gln). This variant is present in population databases (rs121909721, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome or Navajo neurohepatopathy (PMID: 16582910, 16909392, 28209105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16160). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910, 30833296). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging. -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 14, 2022

Variant summary: MPV17 c.149G>A (p.Arg50Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes (gnomAD). c.149G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome (MPV17 Related disorder) and the variant segregated with the disease (examples: Spinazzola_2006 and Karadimas_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting that the R50Q mutation causes protein instability and decay (Karadimas_2006). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

MPV17-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2024

The MPV17 c.149G>A variant is predicted to result in the amino acid substitution p.Arg50Gln. This variant has been previously reported to be pathogenic for the autosomal recessive hepatocerebral form of mitochondrial DNA depletion syndrome (Spinazzola et al. 2006. PubMed ID: 16582910; Shimura et al. 2020. PubMed ID: 32703289). It has been also documented as a founder pathogenic variant for Navajo neurohepatopathy among Navajo children in the southwestern United States (Karadimas et al. 2006. PubMed ID: 16909392). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;D;T;T;T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

M;.;M;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.2

D;D;D;D;N;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;D;D;T;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D;.

Polyphen

0.99

D;D;D;.;.;.;.

Vest4

0.94

MutPred

0.98

Loss of methylation at R48 (P = 0.0705);Loss of methylation at R48 (P = 0.0705);Loss of methylation at R48 (P = 0.0705);.;Loss of methylation at R48 (P = 0.0705);Loss of methylation at R48 (P = 0.0705);.;

MVP

0.96

MPC

1.0

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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