ENST00000361899.2:c.175A>G

Variant names:

• chrM-8701-A-G
• rs2000975
• ENST00000361899.2:c.175A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The ENST00000361899.2(MT-ATP6):​c.175A>G​(p.Thr59Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T59I) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.31 (AC: 19124)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.026
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 No linked disesase in Mitomap
• Conservation: PhyloP100: -5.68
• Publications: 29 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 -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.025634712 < 0.5 .
• BP6: Variant M-8701-A-G is Benign according to our data. Variant chrM-8701-A-G is described in ClinVar as Benign. ClinVar VariationId is 692955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: High frequency in mitomap database: 0.31280002

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.175A>G	p.Thr59Ala	missense	Exon 1 of 1	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.*129A>G		downstream_gene	N/A	ENSP00000355265.1

Frequencies

Mitomap GenBank AF: 0.31 AC: 19124

Gnomad homoplasmic AF: 0.30 AC: 17065 AN: 56285

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56285

Alfa AF: 0.0643 Hom.: 409

Mitomap

No disease associated.

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.026
Hmtvar	Benign	0.070
AlphaMissense	Benign	0.063
DEOGEN2	Benign	0.018	T
LIST_S2	Benign	0.030	T
MutationAssessor	Benign	0.62	N
PhyloP100		-5.7
PROVEAN	Benign	-0.94	N
Sift4G	Benign	0.51	T
Mutation Taster		=90/10	polymorphism

Other links and lift over

dbSNP: rs2000975; hg19: chrM-8702; COSMIC: COSV104419767; COSMIC: COSV104419767;