rs201950015

Variant names:

• chrM-7476-C-T
• rs201950015
• unassigned_transcript_4800:c.39G>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The m.7476C>T variant in MT-TS1 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 seen in 1.310% of individuals in the GenBank dataset (BA1), including in haplogroups J2a (99.7% of individuals) and J2b (98.85% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 1% including in haplogroup J at 20%. If an affected individual is not a member this haplogroup, further evaluation of the variant in that particular individual should be considered. The computational predictor MitoTIP suggests this variant does not impact the function of this tRNA with a score in the 20th percentile, as does HmtVar with a score of 0.1 (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/CA131013/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.013 (AC: 805)
• Consequence: TRNS1 unassigned_transcript_4800 synonymous
• Scores: Mitotip Benign 0.016
• Clinical Significance: Benign reviewed by expert panel B:3 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.836
• Publications: 8 publications found

Genes affected

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE 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
TRNS1	unassigned_transcript_4800	c.39G>A	p.Gln13Gln	synonymous_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.-110C>T		upstream_gene_variant
TRND	unassigned_transcript_4801	c.-42C>T		upstream_gene_variant
COX1	unassigned_transcript_4799	c.*31C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TS1	ENST00000387416.2	n.39G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CO2	ENST00000361739.1	c.-110C>T		upstream_gene_variant		6		ENSP00000354876.1
MT-CO1	ENST00000361624.2	c.*31C>T		downstream_gene_variant		6		ENSP00000354499.2
MT-TD	ENST00000387419.1	n.-42C>T		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.013 AC: 805

Gnomad homoplasmic AF: 0.011 AC: 622 AN: 56432

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56432

Alfa AF: 0.0133 Hom.: 617

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Oct 16, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

m.7476C>T in MT-TS1: This variant is not expected to have clinical significance because it has been observed at equal frequencies in Caucasian individuals with hearing loss and in the general population (Houshmand 1994, Thomas 1996, Sternbe rg 1998, Li 2004, Konings 2008, mtDB-Human Mitochondrial Genome Database). -

Mitochondrial disease Benign:1

Jan 10, 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.7476C>T variant in MT-TS1 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 seen in 1.310% of individuals in the GenBank dataset (BA1), including in haplogroups J2a (99.7% of individuals) and J2b (98.85% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 1% including in haplogroup J at 20%. If an affected individual is not a member this haplogroup, further evaluation of the variant in that particular individual should be considered. The computational predictor MitoTIP suggests this variant does not impact the function of this tRNA with a score in the 20th percentile, as does HmtVar with a score of 0.1 (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.7476C>T variant in MT-TS1 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, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	0.016
Hmtvar	Benign	0.10
PhyloP100		-0.84

Other links and lift over

dbSNP: rs201950015; hg19: chrM-7477;