ENST00000361899.2:c.575T>G

Variant names:

• chrM-9101-T-G
• rs199476134
• ENST00000361899.2:c.575T>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.575T>G​(p.Ile192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 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. I192T) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 18)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.052
• Clinical Significance: Benign criteria provided, single submitter B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 3.20
• Publications: 12 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 -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.05239923 < 0.5 .
• BP6: Variant M-9101-T-G is Benign according to our data. Variant chrM-9101-T-G is described in ClinVar as Benign. ClinVar VariationId is 693092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.575T>G	p.Ile192Ser	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-106T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.575T>G	p.Ile192Ser	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2	c.-106T>G		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.00030 AC: 18

Gnomad homoplasmic AF: 0.00014 AC: 8 AN: 56433

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56433

Mitomap

No disease associated.

ClinVar

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.9101T>G (YP_003024031.1:p.Ile192Ser) 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	0.052
Hmtvar	Benign	0.29
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
DEOGEN2	Benign	0.014	T
LIST_S2	Benign	0.66	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.2
PROVEAN	Benign	0.80	N
Sift4G	Uncertain	0.053	T
GERP RS		4.0
Varity_R		0.15
Mutation Taster		=87/13	polymorphism

Other links and lift over

dbSNP: rs199476134; hg19: chrM-9102;