rs267607267

chr2-27311908-A-AG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002437.5(MPV17):c.451_452insC(p.Leu151ProfsTer39) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000889 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MPV17 NM_002437.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.36

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-27311908-A-AG is Pathogenic according to our data. Variant chr2-27311908-A-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38356.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPV17	NM_002437.5	c.451_452insC	p.Leu151ProfsTer39	frameshift_variant	7/8	ENST00000380044.6
MPV17	XM_005264326.5	c.451_452insC	p.Leu151ProfsTer39	frameshift_variant	7/8
MPV17	XM_017004151.2	c.403_404insC	p.Leu135ProfsTer39	frameshift_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17	ENST00000380044.6	c.451_452insC	p.Leu151ProfsTer39	frameshift_variant	7/8	1	NM_002437.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461548 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000327

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.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 21, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change results in a frameshift in the MPV17 gene (p.Leu151Profs*39). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the MPV17 protein and extend the protein by 12 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 27536553, 29282788). ClinVar contains an entry for this variant (Variation ID: 38356). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 18, 2023

- -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs267607267; hg19: chr2-27534776;