rs886044113

Variant names:

• chr2-27311899-C-A
• rs886044113
• NM_002437.5:c.461G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-27311899-C-A
• chr2-27311899-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PP3: Splicing scoreres supports a deletorius 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 id is 418311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311899-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPV17	NM_002437.5	c.461G>T	p.Arg154Met	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000380044.6	NP_002428.1
MPV17	XM_005264326.5	c.461G>T	p.Arg154Met	missense_variant, splice_region_variant	Exon 7 of 8		XP_005264383.1
MPV17	XM_017004151.2	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	c.461G>T	p.Arg154Met	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_002437.5	ENSP00000369383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:2

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. -

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

- -

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	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	35
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	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H;.;.;.;.
PrimateAI	Uncertain	0.64	T
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	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs886044113; hg19: chr2-27534767; COSMIC: COSV99274470; COSMIC: COSV99274470;