rs267607259

Positions:

• chr2-27309958-G-C
• chr2-27309958-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_002437.5(MPV17):​c.485C>G​(p.Ala162Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A162D) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MPV17 NM_002437.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPV17	NM_002437.5	c.485C>G	p.Ala162Gly	missense_variant	8/8	ENST00000380044.6	NP_002428.1
MPV17	XM_005264326.5	c.485C>G	p.Ala162Gly	missense_variant	8/8		XP_005264383.1
MPV17	XM_017004151.2	c.437C>G	p.Ala146Gly	missense_variant	8/8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6	c.485C>G	p.Ala162Gly	missense_variant	8/8	1	NM_002437.5	ENSP00000369383	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D;D;D;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;N;D;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0090	D;D;D;T;T
Sift4G	Benign	0.12	T;T;D;T;T
Polyphen		0.55	P;P;.;.;.
Vest4		0.62
MutPred		0.81		Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);.;.;.;
MVP		0.91
MPC		0.89
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.34
gMVP		0.51

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: rs267607259; hg19: chr2-27532826;