rs121909725

Positions:

• chr2-27322448-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002437.5(MPV17):​c.70G>T​(p.Gly24Trp) 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPV17 NM_002437.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.82

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 8 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPV17	NM_002437.5	c.70G>T	p.Gly24Trp	missense_variant, splice_region_variant	2/8	ENST00000380044.6
MPV17	XM_005264326.5	c.70G>T	p.Gly24Trp	missense_variant, splice_region_variant	2/8
MPV17	XM_017004151.2	c.-75G>T		splice_region_variant, 5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17	ENST00000380044.6	c.70G>T	p.Gly24Trp	missense_variant, splice_region_variant	2/8	1	NM_002437.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Aug 13, 2019	This variant is interpreted as a variant of uncertain significance for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PM3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.33	.;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PROVEAN	Benign	-0.41	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.060	T;T
Vest4		0.56
MutPred		0.47		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.78
ClinPred		1.0	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909725; hg19: chr2-27545315;