rs201863060

Variant names:

• chrM-12338-T-C
• rs201863060
• ENST00000361567.2:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PVS1 BP6_Moderate BS2

The ENST00000361567.2(MT-ND5):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0033 (AC: 201)
• Consequence: MT-ND5 ENST00000361567.2 start_lost
• Scores: Apogee2 Benign 0.29
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 DEAF1555-increased-penetrance-/-LHON-/-MIDD
• Conservation: PhyloP100: 2.29
• Publications: 10 publications found

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]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) 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; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

TRNS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 3 codons. Genomic position: 12343. Lost 0.004 part of the original CDS.
• BP6: Variant M-12338-T-C is Benign according to our data. Variant chrM-12338-T-C is described in ClinVar as Benign. ClinVar VariationId is 29999.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 70

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.2T>C	p.Met1?	start_lost	Exon 1 of 1
ND4	unassigned_transcript_4811	c.*201T>C		downstream_gene_variant
TRNL2	unassigned_transcript_4814	c.*2T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	6		ENSP00000354813.2
MT-ND4	ENST00000361381.2	c.*201T>C		downstream_gene_variant		6		ENSP00000354961.2

Frequencies

Mitomap GenBank AF: 0.0033 AC: 201

Gnomad homoplasmic AF: 0.0012 AC: 70 AN: 56430

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56430

Alfa AF: 0.000740 Hom.: 12

Mitomap

Disease(s): DEAF1555-increased-penetrance-/-LHON-/-MIDD

Status: Conflicting-reports

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1

May 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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.12338T>C (YP_003024036.1:p.Met1?) 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: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.29
Hmtvar	Pathogenic	0.49
BayesDel_addAF	Benign	-0.43	T
PhyloP100		2.3
GERP RS		3.3
Varity_R		0.47
Mutation Taster		=110/90	polymorphism

Other links and lift over

dbSNP: rs201863060; hg19: chrM-12339;