rs375986475

Variant names:

• chrM-4388-A-G
• rs375986475
• unassigned_transcript_4791:c.13T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The ENST00000000000(TRNQ):​c.13T>C​(p.Trp5Arg) variant causes a missense change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Mitomap GenBank: 𝑓 0.0011 (AC: 67)
• Consequence: TRNQ ENST00000000000 missense
• Scores: Mitotip Benign -0.69
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 Poss.-hypertension-factor|-intellectual-disability
• Conservation: PhyloP100: 5.82
• Publications: 1 publications found

Genes affected

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) 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; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant M-4388-A-G is Benign according to our data. Variant chrM-4388-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235438.
• BS2: High AC in GnomadMitoHomoplasmic at 84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNQ	unassigned_transcript_4791	c.13T>C	p.Trp5Arg	missense_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-82A>G		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-14A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.-82A>G		upstream_gene_variant		6		ENSP00000355046.4
MT-ND1	ENST00000361390.2	c.*126A>G		downstream_gene_variant		6		ENSP00000354687.2

Frequencies

Mitomap GenBank AF: 0.0011 AC: 67

Gnomad homoplasmic AF: 0.0015 AC: 84 AN: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Alfa AF: 0.000727 Hom.: 0

Mitomap

Disease(s): Poss.-hypertension-factor|-intellectual-disability

Status: Reported

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Dec 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MELAS syndrome Benign:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.4388A>G variant in MT-TQ gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	-0.69
Hmtvar	Benign	0.15
PhyloP100		5.8

Other links and lift over

dbSNP: rs375986475; hg19: chrM-4389;