rs121909721

chr2-27313031-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 5.46

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.

• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-27313032-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
MPV17	NM_002437.5	c.149G>A	p.Arg50Gln	missense_variant	3/8	ENST00000380044.6
MPV17	XM_005264326.5	c.149G>A	p.Arg50Gln	missense_variant	3/8
MPV17	XM_017004151.2	c.101G>A	p.Arg34Gln	missense_variant	3/8

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251478 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

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: 16 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

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.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:2 Other:1

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

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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	30
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	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Benign	0.43	T
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	D
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

Other links and lift over

dbSNP: rs121909721; hg19: chr2-27535898; COSMIC: COSV99274548; COSMIC: COSV99274548;