M-12018-C-T

Variant names:

• chrM-12018-C-T
• rs1057516068
• ENST00000361381.2:c.1259C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000361381.2(MT-ND4):​c.1259C>T​(p.Thr420Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T420S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND4 ENST00000361381.2 missense
• Scores: Apogee2 Benign 0.35
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 2.32
• Publications: 0 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]

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: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• BP4: Apogee2 supports a benign effect, 0.3510864 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND4	unassigned_transcript_4811	c.1259C>T	p.Thr420Ile	missense_variant	Exon 1 of 1
TRNL2	unassigned_transcript_4814	c.-248C>T		upstream_gene_variant
TRNH	unassigned_transcript_4812	c.-120C>T		upstream_gene_variant
TRNS2	unassigned_transcript_4813	c.-189C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND4	ENST00000361381.2	c.1259C>T	p.Thr420Ile	missense_variant	Exon 1 of 1	6		ENSP00000354961.2
MT-TH	ENST00000387441.1	n.-120C>T		upstream_gene_variant		6
MT-TS2	ENST00000387449.1	n.-189C>T		upstream_gene_variant		6
MT-TL2	ENST00000387456.1	n.-248C>T		upstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.35
Hmtvar	Pathogenic	0.56
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.35	T
DEOGEN2	Benign	0.069	T
LIST_S2	Benign	0.67	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.3
PROVEAN	Uncertain	-3.6	D
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
GERP RS		3.7
Varity_R		0.14

Other links and lift over

dbSNP: rs1057516068; hg19: chrM-12019;