M-8553-C-T

Position:

• chrM-8553-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The ENST00000361851.1(MT-ATP8):​c.188C>T​(p.Ser63Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63P) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 14)
• Consequence: MT-ATP8 ENST00000361851.1 missense
• Scores: Apogee2 Benign 0.14
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.523

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 -6 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.13674735 < 0.5 .
• BP6: Variant M-8553-C-T is Benign according to our data. Variant chrM-8553-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618720.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 23

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8	ATP8.1	c.188C>T	p.Ser63Leu	missense_variant	1/1		YP_003024030.1
ATP6	ATP6.1	c.27C>T	p.Phe9=	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.188C>T	p.Ser63Leu	missense_variant	1/1			ENSP00000355265	P1
MT-ATP6	ENST00000361899.2	c.27C>T	p.Phe9=	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: 0.00020 AC: 14

Gnomad homoplasmic AF: 0.00041 AC: 23 AN: 56432

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56432

Alfa AF: 0.000223 Hom.: 1

Mitomap

No disease associated.

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 12, 2018

The m.8553C>T variant affects two mitochondrially-encoded genes; MT-ATP8 (c.188C>T; p.Ser63Leu) and MT-ATP6 (c.27C>T; p. Phe9Phe), and has not been associated with any disease. This variant affects a weakly conserved nucleotide, but is rare in the general population (identified in nine individuals in the MITOMAP database; 0.02% population frequency) and is not associated with any particular haplogroup. Therefore, due to limited information, the clinical significance of the m.8553C>T variant is uncertain at this time. -

Leigh syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

The NC_012920.1:m.8553C>T (YP_003024030.1:p.Ser63Leu) variant in MTATP8 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.14
Hmtvar	Pathogenic	0.66
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.85	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-3.0	D
Sift	Benign	0.050	D
Sift4G	Benign	0.14	T
GERP RS		0.66
Varity_R		0.071

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1569484219; hg19: chrM-8554;