rs267607260

Positions:

• chr2-27309934-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002437.5(MPV17):​c.509C>T​(p.Ser170Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPV17 NM_002437.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.61

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 18 ACMG points.

• PS1: Transcript NM_002437.5 (MPV17) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 36 pathogenic changes around while only 6 benign (86%) in NM_002437.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-27309934-G-A is Pathogenic according to our data. Variant chr2-27309934-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPV17	NM_002437.5	c.509C>T	p.Ser170Phe	missense_variant	8/8	ENST00000380044.6
MPV17	XM_005264326.5	c.509C>T	p.Ser170Phe	missense_variant	8/8
MPV17	XM_017004151.2	c.461C>T	p.Ser154Phe	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17	ENST00000380044.6	c.509C>T	p.Ser170Phe	missense_variant	8/8	1	NM_002437.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MPV17 protein function. ClinVar contains an entry for this variant (Variation ID: 38358). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 19520594). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 170 of the MPV17 protein (p.Ser170Phe). -

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

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Aug 13, 2019

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, PP1, PM3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.78
MutPred		0.95		Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);.;.;.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.83

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: rs267607260; hg19: chr2-27532802;