rs745748841

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005765.3(ATP6AP2):c.315T>A(p.Ser105Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,203,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

ATP6AP2
NM_005765.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.411

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ATP6AP2-related disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
congenital disorder of glycosylation, type IIr
Inheritance: AR, XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
syndromic X-linked intellectual disability Hedera type
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
X-linked parkinsonism-spasticity syndrome
Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ATP6AP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21570784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP2	NM_005765.3 link	c.315T>A	p.Ser105Arg	missense_variant	Exon 4 of 9	ENST00000636580.2	NP_005756.2	O75787-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP2	ENST00000636580.2 link	c.315T>A	p.Ser105Arg	missense_variant	Exon 4 of 9	1	NM_005765.3	ENSP00000490083.1		O75787-1

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1090736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26250

American (AMR)

AF:

0.00

AC:

AN:

35189

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19330

East Asian (EAS)

AF:

0.00

AC:

AN:

30157

South Asian (SAS)

AF:

0.00

AC:

AN:

53896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4091

European-Non Finnish (NFE)

AF:

0.00000239

AC:

AN:

835467

Other (OTH)

AF:

0.00

AC:

AN:

45837

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30991

American (AMR)

AF:

0.00

AC:

AN:

10613

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3643

South Asian (SAS)

AF:

0.00

AC:

AN:

2787

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6151

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53326

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability Hedera type

Uncertain:1

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP6AP2-related conditions. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 105 of the ATP6AP2 protein (p.Ser105Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

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

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.074

MetaRNN

Benign

0.22

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

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.9

.;L;.;.;.;.;.;.;.

PhyloP100

0.41

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.0

D;.;.;.;.;N;.;.;N

REVEL

Benign

0.15

Sift

Uncertain

0.0030

D;.;.;.;.;D;.;.;T

Sift4G

Uncertain

0.0030

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

Polyphen

0.88

.;P;.;.;.;.;.;.;.

Vest4

0.55

MutPred

0.42

.;Loss of glycosylation at S105 (P = 0.0289);.;.;Loss of glycosylation at S105 (P = 0.0289);Loss of glycosylation at S105 (P = 0.0289);Loss of glycosylation at S105 (P = 0.0289);.;Loss of glycosylation at S105 (P = 0.0289);

MVP

0.55

MPC

1.0

ClinPred

0.80

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.66

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over