rs878853013

Variant names:

• chrM-8932-C-T
• rs878853013
• unassigned_transcript_4805:c.406C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0040 (AC: 245)
• Consequence: ATP6 missense
• Scores: Apogee2 Benign 0.14
• Clinical Significance: Benign reviewed by expert panel B:3 Prostate-tumor-/-Neuromuscular-disorder
• Conservation: PhyloP100: -0.0870

Genes affected

ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant M-8932-C-T is Benign according to our data. Variant chrM-8932-C-T is described in ClinVar as [Benign]. Clinvar id is 235343.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.406C>T	p.Pro136Ser	missense_variant	Exon 1 of 1

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: 0.0040 AC: 245

Gnomad homoplasmic AF: 0.013 AC: 749 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56428

Alfa AF: 0.00156 Hom.: 7

Mitomap

Prostate-tumor-/-Neuromuscular-disorder

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Benign:1

Oct 17, 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.8932C>T (YP_003024031.1:p.Pro136Ser) variant in MTATP6 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 -

Mitochondrial disease Benign:1

Mar 22, 2021

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The m.8932C>T (p.P136S) variant in MT-ATP6 reaches benign stand-alone criteria (BA1) based on overall allele frequency [gnomAD.v3.1: Overall AF is 1.327% (759/56428); in top-level haplogroup L3, AF is 12.89% (731/5669) Mitomap: Overall AF in Mitomap is 0.399% (207/51863; in top-level haplogroup L3, AF is 9.73%. For the individuals in sub-group L3f, the frequency is 81% (205/253)]. Furthermore, this variant is reported in Phylotree as an L3f1b branch marker. There is one reported proband in the medical literature with this variant (PMID: 26993169), however when haplotyped by this curation team using the variants listed in the published report, the proband belonged to haplogroup L3f (haplogroup with which this variant is associated). In silico tools (APOGEE) predict this variant to be neutral (BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. However, if this variant is identified in an individual who is a member of a different haplogroup than described above, consider further evaluation of this variant. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. -

not provided Benign:1

Mar 18, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.14
Hmtvar	Pathogenic	0.74
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.17	T
DEOGEN2	Benign	0.079	T
LIST_S2	Benign	0.47	T
MutationAssessor	Pathogenic	3.8	H
PROVEAN	Pathogenic	-5.1	D
Sift4G	Uncertain	0.033	D
GERP RS		0.46
Varity_R		0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853013; hg19: chrM-8933; COSMIC: COSV104419801; COSMIC: COSV104419801;