rs387906731

Variant names:

• chrM-10450-A-G
• rs387906731
• unassigned_transcript_4809:c.46A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000000000(TRNR):​c.46A>G​(p.Met16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNR ENST00000000000 missense
• Scores: Mitotip Uncertain 15
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 Combined-OXPHOS-defects-&-severe-multisystem-disorder
• Conservation: PhyloP100: 0.362
• Publications: 1 publications found

Genes affected

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

MT-ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND3 Gene-Disease associations (from GenCC):

• Leigh syndrome

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

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber plus disease

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very low frequency in mitomap database: 0.0

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNR	unassigned_transcript_4809	c.46A>G	p.Met16Val	missense_variant	Exon 1 of 1
ND4L	unassigned_transcript_4810	c.-20A>G		upstream_gene_variant
ND3	unassigned_transcript_4808	c.*46A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TR	ENST00000387439.1	n.46A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND4L	ENST00000361335.1	c.-20A>G		upstream_gene_variant		6		ENSP00000354728.1
MT-ND3	ENST00000361227.2	c.*46A>G		downstream_gene_variant		6		ENSP00000355206.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Combined-OXPHOS-defects-&-severe-multisystem-disorder

Status: Reported

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial encephalomyopathy Pathogenic:1

Mar 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	0.65
PhyloP100		0.36

Other links and lift over

dbSNP: rs387906731; hg19: chrM-10451;