rs41456348

Variant names:

• chrM-4336-T-C
• rs41456348
• unassigned_transcript_4791:c.65A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The m.4336T>C variant in MT-TQ was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on February 12, 2024. This variant has not been reported in the medical literature as causative in individuals or families with primary mitochondrial disease to our knowledge. However, this variant has been reported to be associated with Parkinson and Alzheimer diseases. There are many occurrences of this variant in healthy population databases, including in gnomAD v3.1.2 (737/56,424 or 1.306%), in the Helix dataset (3,949/195,983 or 2.015%), and in the GenBank dataset (535/61,134 or 0.875%), and this variant is seen across haplogroups including haplogroups H, U, A, B, J, HV, K, L3, M, Z, T, C, and V (BA1). Computational predictors are discordant as MitoTIP suggests this variant is benign (37.7 percentile) and HmtVAR predicts it to be pathogenic (0.4). In summary, as association studies linking this variant with Parkinson and Alzheimer diseases are outside the scope of this curation, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340926/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0088 (AC: 535)
• Consequence: TRNQ unassigned_transcript_4791 stop_lost
• Scores: Mitotip Uncertain 11
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:4 ADPD-/-Hearing-Loss-&-Migraine-/-autism-spectrum-/-intellectual-disability
• Conservation: PhyloP100: -1.81
• Publications: 10 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
• hypertrophic cardiomyopathy

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387372.1. 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-TQ	ENST00000387372.1	TSL:6	n.65A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.-134T>C		upstream_gene	N/A	ENSP00000355046.4	P03891
	MT-ND1	ENST00000361390.2	TSL:6	c.*74T>C		downstream_gene	N/A	ENSP00000354687.2	P03886

Frequencies

Mitomap GenBank AF: 0.0088 AC: 535

Gnomad homoplasmic AF: 0.013 AC: 737 AN: 56424

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56424

Alfa AF: 0.0197 Hom.: 1904

Mitomap

Disease(s): ADPD-/-Hearing-Loss-&-Migraine-/-autism-spectrum-/-intellectual-disability

Status: Unclear

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	MELAS syndrome (1)
-	-	1	Mitochondrial disease (1)
-	1	-	not provided (1)
1	-	-	Sensorineural deafness and migraine (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.40
PhyloP100		-1.8

Other links and lift over

dbSNP: rs41456348; hg19: chrM-4337;