rs201863060

Variant names:

• chrM-12338-T-C
• rs201863060
• ENST00000361567.2:c.2T>C
• MT-ND5 p.Met1?

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PVS1 BP6_Moderate BS2

The ENST00000361567.2(MT-ND5):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0033 (AC: 201)
• Consequence: MT-ND5 ENST00000361567.2 start_lost
• Scores: Apogee2 Benign 0.29
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 DEAF1555-increased-penetrance-/-LHON-/-MIDD
• Conservation: PhyloP100: 2.29
• Publications: 10 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: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 18 pathogenic variants. Next in-frame start position is after 3 codons. Genomic position: 12343. Lost 0.004 part of the original CDS.
• BP6: Variant M-12338-T-C is Benign according to our data. Variant chrM-12338-T-C is described in ClinVar as Benign. ClinVar VariationId is 29999.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 70

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND5	ENST00000361567.2	TSL:6	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	ENSP00000354813.2	P03915
	MT-ND4	ENST00000361381.2	TSL:6	c.*201T>C		downstream_gene	N/A	ENSP00000354961.2	P03905
	MT-TH	ENST00000387441.1	TSL:6	n.*132T>C		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0033 AC: 201

Gnomad homoplasmic AF: 0.0012 AC: 70 AN: 56430

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56430

Alfa AF: 0.000740 Hom.: 12

Mitomap

Disease(s): DEAF1555-increased-penetrance-/-LHON-/-MIDD

Status: Conflicting-reports

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
-	-	1	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.29
Hmtvar	Pathogenic	0.49
BayesDel_addAF	Benign	-0.43	T
PhyloP100		2.3
Varity_R		0.47
Mutation Taster		=110/90	polymorphism

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201863060;

hg19: chrM-12339;