rs878853013

Variant names:

• chrM-8932-C-T
• rs878853013
• ENST00000361899.2:c.406C>T

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.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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581280/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0040 (AC: 245)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.14
• Clinical Significance: Benign reviewed by expert panel B:3 Prostate-tumor-/-Neuromuscular-disorder
• Conservation: PhyloP100: -0.0870
• Publications: 21 publications found

Genes affected

MT-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]

MT-ATP6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• NARP syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited spastic paraplegia

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• periodic paralysis with later-onset distal motor neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.406C>T	p.Pro136Ser	missense	Exon 1 of 1	ENSP00000354632.2	P00846

Frequencies

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

Disease(s): Prostate-tumor-/-Neuromuscular-disorder

Status: Reported-[B]

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.087
PROVEAN	Pathogenic	-5.1	D
Sift4G	Uncertain	0.033	D
GERP RS		0.46
Varity_R		0.55
Mutation Taster		=94/6	polymorphism

Other links and lift over

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