M-9101-T-C

Variant names:

• chrM-9101-T-C
• rs199476134
• ENST00000361899.2:c.575T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361899.2(MT-ATP6):​c.575T>C​(p.Ile192Thr) 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I192S) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0010 (AC: 62)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.17
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2 O:1 LHON
• 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 -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.17466378 < 0.5 .
• BP6: Variant M-9101-T-C is Benign according to our data. Variant chrM-9101-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 59

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.575T>C	p.Ile192Thr	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-106T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.575T>C	p.Ile192Thr	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2	c.-106T>C		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.0010 AC: 62

Gnomad homoplasmic AF: 0.0010 AC: 59 AN: 56427

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56427

Alfa AF: 0.000423 Hom.: 2

Mitomap

Disease(s): LHON

Status: Reported

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Other:1

May 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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>C (YP_003024031.1:p.Ile192Thr) 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.17
Hmtvar	Benign	0.11
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
DEOGEN2	Benign	0.015	T
LIST_S2	Benign	0.64	T
MutationAssessor	Benign	-1.6	N
PhyloP100		3.2
PROVEAN	Benign	3.4	N
Sift4G	Benign	1.0	T
GERP RS		4.0
Varity_R		0.091

Other links and lift over

dbSNP: rs199476134; hg19: chrM-9102;