rs1057520079

Positions:

• chrM-9091-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361899.2(MT-ATP6):​c.565A>G​(p.Thr189Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 20)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.0064
• Clinical Significance: Benign reviewed by expert panel U:1 B:2 No linked disesase in Mitomap
• Conservation: PhyloP100: 0.419

Genes affected

ATP6 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.006389093 < 0.5 .
• BP6: Variant M-9091-A-G is Benign according to our data. Variant chrM-9091-A-G is described in ClinVar as [Benign]. Clinvar id is 376876.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 20

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6	ATP6.1	c.565A>G	p.Thr189Ala	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.565A>G	p.Thr189Ala	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.00030 AC: 20

Gnomad homoplasmic AF: 0.00035 AC: 20 AN: 56432

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56432

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 16, 2017

- -

Mitochondrial disease Benign:1

Benign, reviewed by expert panel

curation

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

Jun 26, 2023

The m.9091A>G (p.T189A) variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. There has been a report of this variant being present in an individual from a control cohort (PMID: 15120634). This variant has also been reported in the homoplasmic state in a family with Leber Hereditary Optic Neuropathy (from haplogroup H10) caused by the m.3733G>A variant (PMID: 22879922). There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 21/59,389 (0.035%). The frequency in the Helix dataset is 108/195,983 (0.055%), including 107 homoplasmic occurrences and 1 heteroplasmic occurrence, and occurring in individuals from haplogroups H, U, HV, K, and R. The frequency in gnomAD v3.1.2 is 20/56432 (0.035%), and these occurrences are homoplasmic in individuals of European and African ancestry. Furthermore, this variant has been reported in 14 out of 14 individuals in the H10 haplogroup in addition to the case described above in haplogroup H10, meeting criteria to be considered a top-level haplogroup defining variant (BA1). The computational predictor APOGEE gives a consensus rating of benign with a score of 0.28 (Min=0, Max=1), which predicts a benign effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied BP4, BA1. -

Leigh syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

The NC_012920.1:m.9091A>G (YP_003024031.1:p.Thr189Ala) variant in MTATP6 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.0064
Hmtvar	Benign	0.12
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
DEOGEN2	Benign	0.0084	T
LIST_S2	Benign	0.59	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.63	N
Sift4G	Benign	1.0	T
GERP RS		-0.84
Varity_R		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: rs1057520079; hg19: chrM-9092;