rs141639003

Positions:

chr18-46098207-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004046.6(ATP5F1A):c.25G>A(p.Ala9Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,607,002 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 10 hom. )

Consequence

ATP5F1A
NM_004046.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 3.97

Variant links:

Genes affected

ATP5F1A (HGNC:823): (ATP synthase F1 subunit alpha) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the different isoforms have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16. [provided by RefSeq, Mar 2012]

ATP5F1A links:

ATP5F1A (HGNC:):

ATP5F1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP5F1A. . Gene score misZ 2.437 (greater than the threshold 3.09). Trascript score misZ 3.1515 (greater than threshold 3.09). GenCC has associacion of gene with mitochondrial complex V (ATP synthase) deficiency nuclear type 4B, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation deficiency 22, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A, mitochondrial disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.008045375).

BP6

Variant 18-46098207-C-T is Benign according to our data. Variant chr18-46098207-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00105 (160/152348) while in subpopulation AMR AF= 0.00764 (117/15308). AF 95% confidence interval is 0.00652. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP5F1A	NM_004046.6 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	1/12	ENST00000398752.11	NP_004037.1	P25705-1V9HW26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP5F1A	ENST00000398752.11 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	1/12	1	NM_004046.6	ENSP00000381736.5		P25705-1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

159

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00205

AC:

487

AN:

237102

Hom.:

AF XY:

0.00140

AC XY:

183

AN XY:

130732

show subpopulations

Gnomad AFR exome

AF:

0.000474

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00134

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000279

Gnomad OTH exome

AF:

0.00152

GnomAD4 exome

AF:

0.000458

AC:

666

AN:

1454654

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

261

AN XY:

723768

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00146

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152348

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00764

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.00198

ESP6500AA

AF:

0.000464

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00124

AC:

150

Asia WGS

AF:

0.00376

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 17, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 11, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

ATP5F1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;.;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.94

.;D;D;D;D

MetaRNN

Benign

0.0080

T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.59

N;N;.;.;.

REVEL

Benign

0.068

Sift

Benign

0.098

T;T;.;.;.

Sift4G

Benign

0.32

T;T;T;.;.

Polyphen

0.0

B;B;.;.;.

Vest4

0.43

MVP

0.64

MPC

0.29

ClinPred

0.042

GERP RS

5.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.8

Varity_R

0.27

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over