rs1556423437

Variant names:

• chrM-8382-C-T
• rs1556423437
• ENST00000361851.1:c.17C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The ENST00000361851.1(MT-ATP8):​c.17C>T​(p.Thr6Ile) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T6S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 9)
• Consequence: MT-ATP8 ENST00000361851.1 missense
• Scores: Apogee2 Benign 0.10
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 Suspected-mito-disease
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

Genes affected

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-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-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

TRNK Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• maternally-inherited cardiomyopathy and hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.10092881 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8	unassigned_transcript_4804	c.17C>T	p.Thr6Ile	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.-145C>T		upstream_gene_variant
COX2	unassigned_transcript_4802	c.*113C>T		downstream_gene_variant
TRNK	unassigned_transcript_4803	c.*18C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP8	ENST00000361851.1	c.17C>T	p.Thr6Ile	missense_variant	Exon 1 of 1	6		ENSP00000355265.1
MT-ATP6	ENST00000361899.2	c.-145C>T		upstream_gene_variant		6		ENSP00000354632.2
MT-CO2	ENST00000361739.1	c.*113C>T		downstream_gene_variant		6		ENSP00000354876.1
MT-TK	ENST00000387421.1	n.*18C>T		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.00010 AC: 9

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56431

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56431

Alfa AF: 0.000223 Hom.: 1

Mitomap

Disease(s): Suspected-mito-disease

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8382C>T (YP_003024030.1:p.Thr6Ile) variant in MTATP8 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP6 -

not provided Uncertain:1

May 30, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.10
Hmtvar	Pathogenic	0.77
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.28	T
DEOGEN2	Benign	0.24	T
LIST_S2	Benign	0.79	T
PhyloP100		4.8
PROVEAN	Pathogenic	-5.0	D
Sift	Benign	0.043	D
Sift4G	Uncertain	0.049	D
GERP RS		4.0
Varity_R		0.22

Other links and lift over

dbSNP: rs1556423437; hg19: chrM-8383;