rs200145866

Variant names:

• chrM-11253-T-C
• rs200145866
• ENST00000361381.2:c.494T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000361381.2(MT-ND4):​c.494T>C​(p.Ile165Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 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. I165V) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0052 (AC: 319)
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.078
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1 LHON-PD
• Conservation: PhyloP100: 1.48
• Publications: 30 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]

MT-ND4 Gene-Disease associations (from GenCC):

• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leigh syndrome

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

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• 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 -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.07761309 < 0.5 .
• BP6: Variant M-11253-T-C is Benign according to our data. Variant chrM-11253-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0052
• BS2: High AC in GnomadMitoHomoplasmic at 380

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

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-ND4	ENST00000361381.2	TSL:6	c.494T>C	p.Ile165Thr	missense	Exon 1 of 1	ENSP00000354961.2	P03905

Frequencies

Mitomap GenBank AF: 0.0052 AC: 319

Gnomad homoplasmic AF: 0.0067 AC: 380 AN: 56425

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56425

Alfa AF: 0.00944 Hom.: 480

Mitomap

Disease(s): LHON-PD

Status: Reported

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	not specified (1)
-	-	-	Leber optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.078
Hmtvar	Benign	0.10
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.44	T
DEOGEN2	Benign	0.030	T
LIST_S2	Benign	0.30	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PROVEAN	Benign	-1.5	N
Sift	Benign	0.060	T
Sift4G	Benign	0.089	T
GERP RS		4.5
Varity_R		0.14

Other links and lift over

dbSNP: rs200145866; hg19: chrM-11254; COSMIC: COSV62294075; COSMIC: COSV62294075;