rs749401561

Positions:

chrX-40591282-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_005765.3(ATP6AP2):c.217C>T(p.Arg73Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000356 in 1,209,044 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. 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. R73Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000026 ( 0 hom. 10 hem. )

Consequence

ATP6AP2
NM_005765.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.77

Variant links:

Genes affected

ATP6AP2 (HGNC:18305): (ATPase H+ transporting accessory protein 2) This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases. [provided by RefSeq, Jul 2008]

ATP6AP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33345246).

BP6

Variant X-40591282-C-T is Benign according to our data. Variant chrX-40591282-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204915.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP2	NM_005765.3 linkuse as main transcript	c.217C>T	p.Arg73Trp	missense_variant	3/9	ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2 linkuse as main transcript	c.217C>T	p.Arg73Trp	missense_variant	3/9	1	NM_005765.3	P3	O75787-1

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

112020

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34176

show subpopulations

Gnomad AFR

AF:

0.000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000382

AC:

AN:

183448

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67896

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1096972

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362924

show subpopulations

Gnomad4 AFR exome

AF:

0.000607

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.000134

AC:

AN:

112072

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34238

show subpopulations

Gnomad4 AFR

AF:

0.000486

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2016	- -

Syndromic X-linked intellectual disability Hedera type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 73 of the ATP6AP2 protein (p.Arg73Trp). This variant is present in population databases (rs749401561, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ATP6AP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP6AP2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.;T;T;.;.;T;.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.33

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.1

.;M;M;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.6

.;.;.;.;.;D;.;.;.;.;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

.;.;.;.;.;D;.;.;.;.;.

Sift4G

Uncertain

0.0050

.;.;.;.;.;D;.;.;.;.;.

Polyphen

1.0

.;D;.;.;.;.;.;D;.;.;.

Vest4

0.60

MVP

0.71

MPC

0.56

ClinPred

0.35

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.93

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