rs386829198

Variant names:

• chrM-14002-A-G
• rs386829198
• ENST00000361567.2:c.1666A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361567.2(MT-ND5):​c.1666A>G​(p.Thr556Ala) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T556I) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0023 (AC: 143)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Benign 0.054
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 High-altitude-pulmonary-edema-susceptibility
• Conservation: PhyloP100: -0.389
• Publications: 9 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-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND6 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: G2P, Orphanet
• Leber plus disease

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

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.054000944 < 0.5 .
• BP6: Variant M-14002-A-G is Benign according to our data. Variant chrM-14002-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 185

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.1666A>G	p.Thr556Ala	missense_variant	Exon 1 of 1
ND6	unassigned_transcript_4816	c.*147T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.1666A>G	p.Thr556Ala	missense_variant	Exon 1 of 1	6		ENSP00000354813.2
MT-ND6	ENST00000361681.2	c.*147T>C		downstream_gene_variant		6		ENSP00000354665.2

Frequencies

Mitomap GenBank AF: 0.0023 AC: 143

Gnomad homoplasmic AF: 0.0033 AC: 185 AN: 56411

Gnomad heteroplasmic AF: 0.000089 AC: 5 AN: 56411

Alfa AF: 0.00155 Hom.: 26

Mitomap

Disease(s): High-altitude-pulmonary-edema-susceptibility

Status: Reported

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.14002A>G (YP_003024036.1:p.Thr556Ala) 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, BP4 -

not provided Benign:1

Mar 09, 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	0.054
Hmtvar	Benign	0.14
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
DEOGEN2	Benign	0.029	T
LIST_S2	Benign	0.079	T
MutationAssessor	Benign	0.95	L
PhyloP100		-0.39
PROVEAN	Benign	-1.5	N
Sift4G	Benign	0.11	T
GERP RS		-0.43
Varity_R		0.31
Mutation Taster		=96/4	polymorphism

Other links and lift over

dbSNP: rs386829198; hg19: chrM-14003;