rs200279497

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.10C>T	p.His4Tyr	missense_variant	Exon 1 of 1
ND4	unassigned_transcript_4811	c.*209C>T		downstream_gene_variant
TRNL2	unassigned_transcript_4814	c.*10C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.10C>T	p.His4Tyr	missense_variant	Exon 1 of 1	6		ENSP00000354813.2
MT-ND4	ENST00000361381.2	c.*209C>T		downstream_gene_variant		6		ENSP00000354961.2

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 v4.3

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;