rs587776439

Variant names:

• chrM-11984-T-C
• rs200911567
• ENST00000361381.2:c.1225T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000361381.2(MT-ND4):​c.1225T>C​(p.Tyr409His) variant causes a missense 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 0.0010 (AC: 63)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.15
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1 Leigh-Syndrome
• Conservation: PhyloP100: -0.0180
• Publications: 8 publications found

Genes affected

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]

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 -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.15468292 < 0.5 .
• BP6: Variant M-11984-T-C is Benign according to our data. Variant chrM-11984-T-C is described in ClinVar as Benign. ClinVar VariationId is 155888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 55

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361381.2. 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-ND4	ENST00000361381.2	TSL:6	c.1225T>C	p.Tyr409His	missense	Exon 1 of 1	ENSP00000354961.2
	MT-TH	ENST00000387441.1	TSL:6	n.-154T>C		upstream_gene	N/A
	MT-TS2	ENST00000387449.1	TSL:6	n.-223T>C		upstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0010 AC: 63

Gnomad homoplasmic AF: 0.00097 AC: 55 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Alfa AF: 0.000760 Hom.: 35

Mitomap

Disease(s): Leigh-Syndrome

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.15
Hmtvar	Pathogenic	0.76
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
DEOGEN2	Benign	0.12	T
LIST_S2	Benign	0.67	T
MutationAssessor	Benign	0.51	N
PhyloP100		-0.018
PROVEAN	Uncertain	-2.7	D
Sift	Benign	0.30	T
Sift4G	Benign	0.24	T
GERP RS		1.4
Varity_R		0.23
Mutation Taster		=82/18	polymorphism

Other links and lift over

dbSNP: rs200911567; hg19: chrM-11985;