Variant chrM-8969-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

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

Frequency

Mitomap GenBank:

Absent

Consequence

ATP6
missense

Scores

Apogee2

Pathogenic

0.84

Clinical Significance

Likely pathogenic reviewed by expert panel P:4

Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease

Conservation

PhyloP100: 9.61

Variant links:

Genes affected

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]

ATP6 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

No frequency data in Mitomap. Probably very rare.

PP5

Variant M-8969-G-A is Pathogenic according to our data. Variant chrM-8969-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191364.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.443G>A	p.Ser148Asn	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome

Cov.:

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

Gnomad homoplasmic

AF:

0.0

AC:

AN:

56424

Gnomad heteroplasmic

AF:

0.000071

AC:

AN:

56424

Mitomap

Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2014

- -

Mitochondrial disease

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

The m.8969G>A (p.S148N) variant in MT-ATP6 has been reported in at least five individuals from four families in the literature with features including nephrotic syndrome, developmental delay, seizures, stroke-like episodes, muscle weakness, brain atrophy, agenesis of the corpus callosum, hearing loss, Wolff-Parkinson-White syndrome, increased fasting level of glucose, liver steatosis, and failure to thrive, with heteroplasmy levels ranging from 61-96% (PS4_moderate; PMIDs: 25037980, 29350304, 27812026, 27450679). Additionally, this expert panel knew of two local families with affected individuals with this variant that the expert panel agreed to include. The variant was de novo in two of the four families reported in the literature (PS2_moderate; PMIDs: 25037980, 27450679). This variant segregated with disease in multiple affected members in one family and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29350304). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMID: 27812026). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.57 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS2_moderate, PP1_moderate, PM2_supporting, PS3_supporting, PP3. -

MELAS syndrome

Pathogenic:1

Pathogenic, 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.8969G>A (YP_003024031.1:p.Ser148Asn) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 -

Leber optic atrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Apogee2

Pathogenic

0.84

Hmtvar

Pathogenic

0.81

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

0.0045

DEOGEN2

Benign

0.33

LIST_S2

Benign

0.77

MutationAssessor

Pathogenic

5.3

PROVEAN

Uncertain

-2.8

Sift4G

Pathogenic

0.0

GERP RS

4.9

Varity_R

0.94

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Mitomap

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over