M-10455-A-G

Variant names:

• chrM-10455-A-G
• rs1603222840
• unassigned_transcript_4809:c.51A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Strong BS2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 12)
• Consequence: TRNR missense
• Scores: Mitotip Benign 4.0
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -1.88

Genes affected

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant M-10455-A-G is Benign according to our data. Variant chrM-10455-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 690123.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 16

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNR	unassigned_transcript_4809	c.51A>G	p.Ile17Met	missense_variant	Exon 1 of 1
ND4L	unassigned_transcript_4810	c.-15A>G		upstream_gene_variant
ND3	unassigned_transcript_4808	c.*51A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.00020 AC: 12

Gnomad homoplasmic AF: 0.00028 AC: 16 AN: 56432

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56432

Alfa AF: 0.000223 Hom.: 1

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Dec 10, 2021

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.10455A>G variant in MT-TR 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 has been reported only once in the literature (PMID: 23463613; Supp Table S1B) in the homoplasmic state in an individual from H haplogroup and mother was not available for testing. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. There are no large families reported in the medical literature to consider for evidence of segregation. There are several occurrences of this variant in GenBank sequences queried through MITOMAP on 6/29/2020 (seen in 1-4 individuals from several haplogroups including J1c, H1b, H1j, U5a, N1a for a total of 12/51,192 frequency). The computational predictor MitoTIP suggests this variant is likely benign (10th percentile) and HmtVAR predicts it to be likely polymorphic (BP4). There are no cybrid or single fiber studies reported on 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 U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: 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.10455A>G variant in MT-TR 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	4.0
Hmtvar	Benign	0.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603222840; hg19: chrM-10456;