rs886044113

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_002437.5(MPV17):c.461G>T(p.Arg154Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MPV17
NM_002437.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.57

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Charcot-Marie-Tooth disease, axonal, type 2EE
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MPV17 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a chain Mitochondrial inner membrane protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 23 pathogenic changes around while only 5 benign (82%) in NM_002437.5

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-27311899-C-A is Pathogenic according to our data. Variant chr2-27311899-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 418311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPV17	NM_002437.5 link	c.461G>T	p.Arg154Met	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000380044.6	NP_002428.1	P39210A0A0S2Z3Z9
MPV17	XM_005264326.5 link	c.461G>T	p.Arg154Met	missense_variant, splice_region_variant	Exon 7 of 8		XP_005264383.1	P39210A0A0S2Z3Z9
MPV17	XM_017004151.2 link	c.413G>T	p.Arg138Met	missense_variant, splice_region_variant	Exon 7 of 8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6 link	c.461G>T	p.Arg154Met	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_002437.5	ENSP00000369383.1		P39210

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Pathogenic:2

Dec 01, 2017

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2019

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PM3-strong. -

not provided

Pathogenic:1

Dec 19, 2014

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A novel R154M (c.461 G>T) variant that is likely pathogenic was identified in the MPV17 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R154M missense change is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (A162D) has been reported in the Human Gene Mutation Database in association with mitochondrial DNA depletion syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, several in-silico splice prediction models predict that the c.461 G>T nucleotide substitution, responsible for R154M, damages the natural splice donor site for exon 7 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.461 G>T sequence change in this individual is unknown. Therefore, R154M (c.461 G>T) is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. -

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

Pathogenic:1

Apr 08, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.93

D;D;D;D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

.;D;D;D;D;T

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

H;H;.;.;.;.

PhyloP100

5.6

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.7

D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.92

MutPred

0.81

Loss of methylation at R154 (P = 0.0194);Loss of methylation at R154 (P = 0.0194);.;.;.;Loss of methylation at R154 (P = 0.0194);

MVP

0.96

MPC

1.1

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.79

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.86

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over