rs1057520079

Variant names:

• chrM-9091-A-G
• rs1057520079
• ENST00000361899.2:c.565A>G

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.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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603197/MONDO:0044970/015

• 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
• Publications: 1 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-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED 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.

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.565A>G	p.Thr189Ala	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-CO3	ENST00000362079.2	TSL:6	c.-116A>G		upstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

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

ClinVar submissions as Germline

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	0.0064
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
PhyloP100		0.42
PROVEAN	Benign	0.63	N
Sift4G	Benign	1.0	T
GERP RS		-0.84
Varity_R		0.10
Mutation Taster		=47/153	disease causing

Other links and lift over

dbSNP: rs1057520079; hg19: chrM-9092;