rs41347846

Variant names:

• chrM-10034-T-C
• rs41347846
• unassigned_transcript_4807:c.44T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The m.10034T>C variant in MT-TG was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant is associated with haplogroup I (almost 100% of individuals in this haplogroup have this variant) and the overall allele frequency in the GenBank database is 1.553% (BA1). Additionally, the computational predictor MitoTIP suggests this variant is benign (6.7th percentile) and HmtVAR predicts it to be polymorphic (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA337098672/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.016 (AC: 991)
• Consequence: TRNG unassigned_transcript_4807 missense
• Scores: Mitotip Benign 3.0
• Clinical Significance: Benign reviewed by expert panel B:3 No linked disesase in Mitomap
• Conservation: PhyloP100: -2.35
• Publications: 11 publications found

Genes affected

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

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-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNG	unassigned_transcript_4807	c.44T>C	p.Val15Ala	missense_variant	Exon 1 of 1
ND3	unassigned_transcript_4808	c.-25T>C		upstream_gene_variant
COX3	unassigned_transcript_4806	c.*44T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TG	ENST00000387429.1	n.44T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND3	ENST00000361227.2	c.-25T>C		upstream_gene_variant		6		ENSP00000355206.2
MT-CO3	ENST00000362079.2	c.*44T>C		downstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.016 AC: 991

Gnomad homoplasmic AF: 0.018 AC: 1008 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56428

Alfa AF: 0.0227 Hom.: 1136

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mitochondrial disease Benign:1

Mar 24, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The m.10034T>C variant in MT-TG was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is associated with haplogroup I (almost 100% of individuals in this haplogroup have this variant) and the overall allele frequency in the GenBank database is 1.553% (BA1). Additionally, the computational predictor MitoTIP suggests this variant is benign (6.7th percentile) and HmtVAR predicts it to be polymorphic (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4.

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.10034T>C variant in MT-TG 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: BA1, BP4

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	3.0
Hmtvar	Benign	0.0
PhyloP100		-2.3

Other links and lift over

dbSNP: rs41347846; hg19: chrM-10035;