rs878853003

Positions:

• chrM-8527-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 10P and 12B. PVS1 PS1_Moderate BP6_Very_Strong BS2

The ENST00000361899.2(MT-ATP6):​c.1A>G​(p.Met1?) variant causes a start lost change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.0040 (AC: 245)
• Consequence: MT-ATP6 ENST00000361899.2 start_lost
• Scores: Apogee2 Benign 0.23
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 Neuromuscular-disorder+-possible-helper-mutation
• Conservation: PhyloP100: 5.91

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000361899.2 (MT-ATP6) was described as [Likely_pathogenic] in ClinVar as 9640
• BP6: Variant M-8527-A-G is Benign according to our data. Variant chrM-8527-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 736

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	ATP6.1	c.1A>G	p.Met1?	start_lost	1/1		YP_003024031.1
ATP8	ATP8.1	c.162A>G	p.Lys54=	synonymous_variant	1/1		YP_003024030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.1A>G	p.Met1?	start_lost	1/1			ENSP00000354632	P1
MT-ATP8	ENST00000361851.1	c.162A>G	p.Lys54=	synonymous_variant	1/1			ENSP00000355265	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: 0.0040 AC: 245

Gnomad homoplasmic AF: 0.013 AC: 736 AN: 56430

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56430

Alfa AF: 0.00156 Hom.: 7

Mitomap

Neuromuscular-disorder+-possible-helper-mutation

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.8527A>G (YP_003024031.1:p.Met1Val) 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 -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.23
Hmtvar	Pathogenic	0.53
BayesDel_addAF	Benign	-0.27	T
DEOGEN2	Benign	0.22	T
LIST_S2	Uncertain	0.90	D
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-3.3	D
Sift4G	Pathogenic	0.0010	D
GERP RS		3.7
Varity_R		0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853003; hg19: chrM-8528;