M-12346-C-T

Variant names:

• chrM-12346-C-T
• rs200279497
• ENST00000361567.2:c.10C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000361567.2(MT-ND5):​c.10C>T​(p.His4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.0071 (AC: 432)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Benign 0.0016
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 No linked disesase in Mitomap
• Conservation: PhyloP100: -3.18
• Publications: 5 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: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.0015835421 < 0.5 .
• BP6: Variant M-12346-C-T is Benign according to our data. Variant chrM-12346-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0070999996
• BS2: High AC in GnomadMitoHomoplasmic at 202

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361567.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND5	ENST00000361567.2	TSL:6	c.10C>T	p.His4Tyr	missense	Exon 1 of 1	ENSP00000354813.2
	MT-ND4	ENST00000361381.2	TSL:6	c.*209C>T		downstream_gene	N/A	ENSP00000354961.2
	MT-TH	ENST00000387441.1	TSL:6	n.*140C>T		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0071 AC: 432

Gnomad homoplasmic AF: 0.0036 AC: 202 AN: 56434

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56434

Alfa AF: 0.00368 Hom.: 84

Mitomap

No disease associated.

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.12346C>T (YP_003024036.1:p.His4Tyr) 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

not provided Benign:1

Apr 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.0016
Hmtvar	Benign	0.18
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
DEOGEN2	Benign	0.0034	T
LIST_S2	Benign	0.77	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-3.2
PROVEAN	Benign	1.4	N
Sift4G	Benign	1.0	T
GERP RS		-1.9
Varity_R		0.25
Mutation Taster		=98/2	polymorphism

Other links and lift over

dbSNP: rs200279497; hg19: chrM-12347;