rs878853096

Positions:

• chrM-9152-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Strong BS2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 17)
• Consequence: ATP6 missense
• Scores: Apogee2 Pathogenic 0.57
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 O:1 Patient-with-suspected-mitochondrial-disease
• Conservation: PhyloP100: 7.67

Genes affected

ATP6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant M-9152-T-C is Benign according to our data. Variant chrM-9152-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 235698.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	unassigned_transcript_4806	c.626T>C	p.Ile209Thr	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.00030 AC: 17

Gnomad homoplasmic AF: 0.00012 AC: 7 AN: 56430

Gnomad heteroplasmic AF: 0.000089 AC: 5 AN: 56430

Alfa AF: 0.000223 Hom.: 1

Mitomap

Patient-with-suspected-mitochondrial-disease

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Jun 26, 2023

The m.9152T>C (p.I209T) variant in MT-ATP6 has been reported in one case to date, in an individual with autism, fatigue, reflux, and constipation (PMID: 30763462) who had the variant present at 23% in blood. The proband's healthy mother had the variant present at 10% in blood. There are no reported de novo occurrences to our knowledge. The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.47 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 13, 2014

- -

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.9152T>C (YP_003024031.1:p.Ile209Thr) variant in MTATP6 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 -

Mitochondrial-DNA disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.57
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.0048	T
DEOGEN2	Benign	0.40	T
LIST_S2	Benign	0.77	T
MutationAssessor	Pathogenic	5.0	H
PROVEAN	Pathogenic	-4.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853096; hg19: chrM-9153;