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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387429.1. 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-TG	ENST00000387429.1	TSL:6	n.44T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ND3	ENST00000361227.2	TSL:6	c.-25T>C		upstream_gene	N/A	ENSP00000355206.2	P03897
	MT-CO3	ENST00000362079.2	TSL:6	c.*44T>C		downstream_gene	N/A	ENSP00000354982.2	P00414

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	MELAS syndrome (1)
-	-	1	Mitochondrial disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;