chrM-12811-T-C

Variant names:

• chrM-12811-T-C
• rs199974018
• unassigned_transcript_4815:c.475T>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.011 (AC: 681)
• Consequence: ND5 missense
• Scores: Apogee2 Benign 0.012
• Clinical Significance: Benign reviewed by expert panel U:1 B:2 O:1 Possible-LHON-factor
• Conservation: PhyloP100: -1.37

Genes affected

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 Benign. Variant got -16 ACMG points.

• BP6: Variant M-12811-T-C is Benign according to our data. Variant chrM-12811-T-C is described in ClinVar as [Benign]. Clinvar id is 65510.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: High frequency in mitomap database: 0.0111

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.475T>C	p.Tyr159His	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.011 AC: 681

Gnomad homoplasmic AF: 0.0058 AC: 328 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Alfa AF: 0.00201 Hom.: 9

Mitomap

Possible-LHON-factor

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Mar 17, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.12811T>C (YP_003024036.1:p.Tyr1159His) variant in MTND5 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Mitochondrial disease Benign:1

Apr 17, 2023

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The m.12811T>C (p. Y159H) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 17, 2023. This variant has not been reported in the medical literature as an individual cause of primary mitochondrial disease to our knowledge. However, there are nine cases reported that have this variant and the common Leber Hereditary Optic Neuropathy (LHON) variant, m.11778G>A, and one case with this variant and the m.3460G>A common LHON variant (PMIDs: 17406640, 17434142, 19026397). While this variant has been reported to be a modifier or secondary variant for LHON, assessment of such variants is outside the scope of this curation. The computational predictor APOGEE gives a consensus rating of 0.32 (Min=0, Max=1), supporting a neutral effect of this variant on function (BP4). This variant is present in population databases including MITOMAP’s GenBank sequences (674/59,389; 1.135%), in the Helix dataset (1,274/195,983; 0.650%; includes 1274 homoplasmic occurrences and 14 heteroplasmic occurrences and seen in haplogroups H, M, A, K, W, D, L2, T), and in gnomAD v3.1.2 (328/56,429; 0.581%; includes 328 homoplasmic occurrences across individuals of East Asian, European (non-Finnish), Latino, and South Asian descent; BA1). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4, BA1. -

Leber optic atrophy Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.012
Hmtvar	Benign	0.17
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
DEOGEN2	Benign	0.029	T
LIST_S2	Benign	0.45	T
MutationAssessor	Benign	0.68	N
PROVEAN	Benign	-1.8	N
Sift4G	Benign	0.35	T
GERP RS		-1.3
Varity_R		0.43

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199974018; hg19: chrM-12812;