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 Benign/Likely_benign. ClinVar VariationId is 445967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 185

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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND5	ENST00000361567.2	TSL:6	c.1666A>G	p.Thr556Ala	missense	Exon 1 of 1	ENSP00000354813.2
	MT-ND6	ENST00000361681.2	TSL:6	c.*147T>C		downstream_gene	N/A	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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;