M-8538-T-C

Position:

• chrM-8538-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000361851.1(MT-ATP8):​c.173T>C​(p.Ile58Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. I58V) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.00080 (AC: 48)
• Consequence: MT-ATP8 ENST00000361851.1 missense
• Scores: Apogee2 Benign 0.11
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.164

Genes affected

ATP8 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.106946856 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 15

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8	ATP8.1	c.173T>C	p.Ile58Thr	missense_variant	1/1		YP_003024030.1
ATP6	ATP6.1	c.12T>C	p.Asn4=	synonymous_variant	1/1		YP_003024031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ATP8	ENST00000361851.1	c.173T>C	p.Ile58Thr	missense_variant	1/1			ENSP00000355265	P1
MT-ATP6	ENST00000361899.2	c.12T>C	p.Asn4=	synonymous_variant	1/1			ENSP00000354632	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.00080 AC: 48

Gnomad homoplasmic AF: 0.00027 AC: 15 AN: 56411

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56411

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.11
Hmtvar	Pathogenic	0.67
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
DEOGEN2	Benign	0.14	T
LIST_S2	Benign	0.75	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Uncertain	-4.1	D
Sift	Benign	0.067	T
Sift4G	Benign	0.072	T
GERP RS		-2.1
Varity_R		0.14

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853010; hg19: chrM-8539;