rs267606899

Positions:

• chrM-12848-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM2 PP3 PP5

The ENST00000361567.2(MT-ND5):​c.512C>T​(p.Ala171Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1 LHON
• Conservation: PhyloP100: 7.31

Genes affected

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript ENST00000361567.2 (MT-ND5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.9047112 >= 0.5 .
• PP5: Variant M-12848-C-T is Pathogenic according to our data. Variant chrM-12848-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9704.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.512C>T	p.Ala171Val	missense_variant	1/1			ENSP00000354813	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

LHON

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
DEOGEN2	Benign	0.26	T
LIST_S2	Uncertain	0.94	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	A
PROVEAN	Uncertain	-4.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.7
Varity_R		0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606899; hg19: chrM-12849;