M-8557-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000361899.2(MT-ATP6):c.31G>A(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Mitomap GenBank: 𝑓 0.0059 (AC: 361)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.0039
• Clinical Significance: Benign reviewed by expert panel B:2 No linked disesase in Mitomap
• Conservation: PhyloP100: 0.867

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]

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) 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 multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.003913622 < 0.5 .
• BP6: Variant M-8557-G-A is Benign according to our data. Variant chrM-8557-G-A is described in ClinVar as [Benign]. Clinvar id is 692900.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: High frequency in mitomap database: 0.0058999998
• BS2: High AC in GnomadMitoHomoplasmic at 476

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6	ATP6.1	c.31G>A	p.Ala11Thr	missense_variant	1/1
ATP8	ATP8.1	c.192G>A	p.Leu64=	synonymous_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.31G>A	p.Ala11Thr	missense_variant	1/1			P1
MT-ATP8	ENST00000361851.1	c.192G>A	p.Leu64=	synonymous_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: 0.0059 AC: 361

Gnomad homoplasmic AF: 0.0084 AC: 476 AN: 56416

Gnomad heteroplasmic AF: 0.00014 AC: 8 AN: 56416

Alfa AF: 0.0132 Hom.: 59

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Benign:1

Benign, reviewed by expert panel

curation

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

Mar 24, 2022

The m.8857G>A (p.A11T) variant in MT-ATP6 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 is seen at high frequencies across multiple haplogroups in the GenBank dataset (BS1_stand alone) including in haplogroup R7b (100% of individuals however only 9 sequences), H32 (89% of individuals however only 8/9 sequences), M30f (80% of individuals), M11d (67% of individuals), J1B (46% of individuals out of 390 sequences), X1c (40% of individuals), M52b (21% of individuals), D1g (10% of individuals), H7c (8% of individuals), and I2 (7% of individuals). If an affected individual is not a member of one of these haplogroups, further evaluation of the variant in that particular individual should be considered. In summary, this variant meets criteria to be classified as benign given high frequency in the general population across multiple haplogroups. 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: BS1_stand alone. -

Leigh syndrome Benign:1

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.8557G>A (YP_003024031.1:p.Ala11Thr) 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, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.0039
Hmtvar	Benign	0.11
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.50	T
DEOGEN2	Benign	0.0066	T
LIST_S2	Benign	0.086	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	1.2	N
Sift4G	Benign	0.54	T
GERP RS		-3.4
Varity_R		0.091

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386829040; hg19: chrM-8558;