rs193302965

Variant names:

• chrM-13708-G-A
• rs28359178
• ENST00000361567.2:c.1372G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The ENST00000361567.2(MT-ND5):​c.1372G>A​(p.Ala458Thr) 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 0.075 (AC: 4560)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Benign 0.31
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:2 LHON-/-Increased-MS-risk-/-higher-freq-in-PD-ADS
• Conservation: PhyloP100: 0.633
• Publications: 95 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-ND5 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.30702576 < 0.5 .
• BP6: Variant M-13708-G-A is Benign according to our data. Variant chrM-13708-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: High frequency in mitomap database: 0.0746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.1372G>A	p.Ala458Thr	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.1372G>A	p.Ala458Thr	missense_variant	Exon 1 of 1	6		ENSP00000354813.2

Frequencies

Mitomap GenBank AF: 0.075 AC: 4560

Gnomad homoplasmic AF: 0.076 AC: 4263 AN: 56361

Gnomad heteroplasmic AF: 0.00037 AC: 21 AN: 56361

Alfa AF: 0.114 Hom.: 2906

Mitomap

Disease(s): LHON-/-Increased-MS-risk-/-higher-freq-in-PD-ADS

Status: Conflicting-reports

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Uncertain:1

Sep 19, 2013

GeneReviews

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Sep 30, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

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.13708G>A (YP_003024036.1:p.Ala458Thr) 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.31
Hmtvar	Benign	0.21
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
DEOGEN2	Benign	0.030	T
LIST_S2	Benign	0.58	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.63
PROVEAN	Benign	-1.5	N
Sift4G	Benign	0.078	T
GERP RS		-5.7
Varity_R		0.29
Mutation Taster		=95/5	polymorphism

Other links and lift over

dbSNP: rs28359178; hg19: chrM-13709;