rs41456348

Positions:

• chrM-4336-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000387372.1(MT-TQ):​n.65A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0088 (AC: 535)
• Consequence: MT-TQ ENST00000387372.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 11
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:3 ADPD-/-Hearing-Loss-&-Migraine-/-autism-spectrum-/-intellectual-disability
• Conservation: PhyloP100: -1.81

Genes affected

MT-TQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

TRNQ (HGNC:):

MT-TI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant M-4336-T-C is Benign according to our data. Variant chrM-4336-T-C is described in ClinVar as [Benign]. Clinvar id is 9615.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: High frequency in mitomap database: 0.0088
• BS2: High AC in GnomadMitoHomoplasmic at 737

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNQ	TRNQ.1	n.65A>G		non_coding_transcript_exon_variant	1/1
TRNI	TRNI.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TQ	ENST00000387372.1	n.65A>G		non_coding_transcript_exon_variant	1/1
MT-TI	ENST00000387365.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

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: 0.0207 Hom.: 1487

Mitomap

ADPD-/-Hearing-Loss-&-Migraine-/-autism-spectrum-/-intellectual-disability

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Sensorineural deafness and migraine Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 26, 2015

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 17, 2020

- -

Mitochondrial disease Benign:1

Benign, reviewed by expert panel

curation

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

Feb 12, 2024

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. -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 12, 2019

The NC_012920.1:m.4336T>C 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41456348; hg19: chrM-4337;