chrM-7502-C-T

Position:

• chrM-7502-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The m.7502C>T variant in MT-TS1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 24, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual of Han Chinese descent with a tic disorder (PMID:33289513). Other features were not reported and other genetic etiologies were not assessed. There are several occurrences in population databases. This variant is present in 0.007% of individuals in GenBank MITOMAP sequences, in 0.009% of individuals in gnomAD v3.1.2 (homoplasmic in all five individuals), and in 0.004% of individuals in the Helix dataset (six homoplasmic occurrences, one heteroplasmic). MitoTIP suggests this variant is benign (8.2 percentile) and HmtVAR predicts it to be polymorphic (0.1; BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10577185/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 4)
• Consequence: MT-TS1 ENST00000387416.2 non_coding_transcript_exon
• Scores: Mitotip Benign 3.5
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 Reported-in-tic-disorder-patient
• Conservation: PhyloP100: -0.689

Genes affected

MT-TS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

TRNS1 (HGNC:):

MT-TD (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

ACMG classification

Verdict is Uncertain_significance. Variant got -1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNS1	TRNS1.1	n.13G>A		non_coding_transcript_exon_variant	1/1
TRND	TRND.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TS1	ENST00000387416.2	n.13G>A		non_coding_transcript_exon_variant	1/1
MT-TD	ENST00000387419.1			upstream_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: 0.00010 AC: 4

Gnomad homoplasmic AF: 0.000089 AC: 5 AN: 56433

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56433

Mitomap

Reported-in-tic-disorder-patient

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2016

The m.7502C>T variant in MT-TS1 has not been previously reported in individuals with hearing loss. This variant has been identified in 3/30589 human mitochondri al DNA sequences of various ancestries (http://www.mitomap.org). In summary, the clinical significance of the m.7502C>T variant is uncertain. -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jul 24, 2023

The m.7502C>T variant in MT-TS1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 24, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual of Han Chinese descent with a tic disorder (PMID: 33289513). Other features were not reported and other genetic etiologies were not assessed. There are several occurrences in population databases. This variant is present in 0.007% of individuals in GenBank MITOMAP sequences, in 0.009% of individuals in gnomAD v3.1.2 (homoplasmic in all five individuals), and in 0.004% of individuals in the Helix dataset (six homoplasmic occurrences, one heteroplasmic). MitoTIP suggests this variant is benign (8.2 percentile) and HmtVAR predicts it to be polymorphic (0.1; BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. -

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

Likely 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.7502C>T variant in MT-TS1 gene is interpreted to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS2, BP4, BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	3.5
Hmtvar	Benign	0.10

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657868; hg19: chrM-7503;