rs992965475

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001183.6(ATP6AP1):c.37G>C(p.Gly13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,147,658 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000032 ( 0 hom. 11 hem. )

Consequence

ATP6AP1
NM_001183.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.452

Publications

0 publications found

Variant links:

Genes affected

ATP6AP1 (HGNC:868): (ATPase H+ transporting accessory protein 1) This gene encodes a component of a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Vacuolar ATPase (V-ATPase) is comprised of a cytosolic V1 (site of the ATP catalytic site) and a transmembrane V0 domain. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. The encoded protein of this gene may assist in the V-ATPase-mediated acidification of neuroendocrine secretory granules. This protein may also play a role in early development. [provided by RefSeq, Aug 2013]

ATP6AP1 links:

ATP6AP1-DT (HGNC:25138): (ATP6AP1 divergent transcript)

ATP6AP1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.090290904).

BP6

Variant X-154428729-G-C is Benign according to our data. Variant chrX-154428729-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1961380.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Hemizygotes in GnomAdExome4 at 11 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP1	NM_001183.6 link	c.37G>C	p.Gly13Arg	missense_variant	Exon 1 of 10	ENST00000369762.7	NP_001174.2
ATP6AP1-DT	NR_103768.1 link	n.-250C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7 link	c.37G>C	p.Gly13Arg	missense_variant	Exon 1 of 10	1	NM_001183.6	ENSP00000358777.2		Q15904

Frequencies

GnomAD3 genomes

AF:

0.0000352

AC:

AN:

113527

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:

0.0000749

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000357

AC:

AN:

83970

AF XY:

0.0000379

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000567

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000643

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000319

AC:

AN:

1034131

Hom.:

Cov.:

AF XY:

0.0000328

AC XY:

AN XY:

335499

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22483

American (AMR)

AF:

0.0000373

AC:

AN:

26789

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18108

East Asian (EAS)

AF:

0.00

AC:

AN:

25213

South Asian (SAS)

AF:

0.00

AC:

AN:

49114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3964

European-Non Finnish (NFE)

AF:

0.0000393

AC:

AN:

814644

Other (OTH)

AF:

0.00

AC:

AN:

43764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000352

AC:

AN:

113527

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35665

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31320

American (AMR)

AF:

0.00

AC:

AN:

10884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3583

South Asian (SAS)

AF:

0.00

AC:

AN:

2870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6355

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000749

AC:

AN:

53393

Other (OTH)

AF:

0.00

AC:

AN:

1537

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the ATP6AP1 protein (p.Gly13Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ATP6AP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1961380). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Benign:1

Aug 28, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.044

T;T;T

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.48

T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

N;.;.

PhyloP100

0.45

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.49

N;N;N

REVEL

Benign

0.067

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.87

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.23

MutPred

0.50

Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);

MVP

0.17

MPC

0.33

ClinPred

0.027

GERP RS

-1.1

PromoterAI

0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.063

gMVP

0.33

Mutation Taster

=96/4

polymorphism

(source)

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

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rs992965475

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