chrM-8803-A-G

Variant names:

• chrM-8803-A-G
• rs878853020
• ENST00000361899.2:c.277A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000361899.2(MT-ATP6):​c.277A>G​(p.Thr93Ala) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T93S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 9)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.096
• Clinical Significance: Likely benign criteria provided, single submitter B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 7.09
• Publications: 2 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-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]

MT-ATP8 Gene-Disease associations (from GenCC):

• mitochondrial proton-transporting ATP synthase complex deficiency

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR, Mitochondrial Classification: LIMITED Submitted by: Illumina, ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.09584203 < 0.5 .
• BP6: Variant M-8803-A-G is Benign according to our data. Variant chrM-8803-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 692989.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 26

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.277A>G	p.Thr93Ala	missense_variant	Exon 1 of 1
ATP8	unassigned_transcript_4804	c.*231A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.277A>G	p.Thr93Ala	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-ATP8	ENST00000361851.1	c.*231A>G		downstream_gene_variant		6		ENSP00000355265.1

Frequencies

Mitomap GenBank AF: 0.00010 AC: 9

Gnomad homoplasmic AF: 0.00046 AC: 26 AN: 56433

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56433

Mitomap

No disease associated.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8803A>G (YP_003024031.1:p.Thr93Ala) 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, BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.096
Hmtvar	Pathogenic	0.68
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.048	T
DEOGEN2	Benign	0.12	T
LIST_S2	Benign	0.65	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.1
PROVEAN	Uncertain	-4.2	D
Sift4G	Uncertain	0.012	D
GERP RS		3.5
Varity_R		0.65
Mutation Taster		=58/142	disease causing

Other links and lift over

dbSNP: rs878853020; hg19: chrM-8804;