NM_001183.6:c.29T>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001183.6(ATP6AP1):c.29T>A(p.Val10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,148,654 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000056 ( 0 hom. 22 hem. )

Consequence

ATP6AP1
NM_001183.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.158

Publications

1 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10392025).

BS2

High Hemizygotes in GnomAdExome4 at 22 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP1	NM_001183.6 link	c.29T>A	p.Val10Glu	missense_variant	Exon 1 of 10	ENST00000369762.7	NP_001174.2
ATP6AP1-DT	NR_103768.1 link	n.-242A>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7 link	c.29T>A	p.Val10Glu	missense_variant	Exon 1 of 10	1	NM_001183.6	ENSP00000358777.2		Q15904

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

113155

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000351

AC:

AN:

85549

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000560

AC:

AN:

1035499

Hom.:

Cov.:

AF XY:

0.0000654

AC XY:

AN XY:

336253

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22630

American (AMR)

AF:

0.00

AC:

AN:

27109

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18185

East Asian (EAS)

AF:

0.00

AC:

AN:

25312

South Asian (SAS)

AF:

0.00

AC:

AN:

49235

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30159

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3981

European-Non Finnish (NFE)

AF:

0.0000687

AC:

AN:

815056

Other (OTH)

AF:

0.0000456

AC:

AN:

43832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000177

AC:

AN:

113155

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35349

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31219

American (AMR)

AF:

0.00

AC:

AN:

10825

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3573

South Asian (SAS)

AF:

0.00

AC:

AN:

2841

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6307

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53286

Other (OTH)

AF:

0.00

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000388

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 10 of the ATP6AP1 protein (p.Val10Glu). This variant is present in population databases (rs782201766, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP6AP1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

ATP6AP1-related disorder

Uncertain:1

Jun 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATP6AP1 c.29T>A variant is predicted to result in the amino acid substitution p.Val10Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0095% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.0

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.093

T;T;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.38

T;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

-0.16

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.86

N;N;N

REVEL

Benign

0.034

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.14

T;T;D

Polyphen

0.089

B;.;.

Vest4

0.27

MutPred

0.44

Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);

MVP

0.21

MPC

0.43

ClinPred

0.074

GERP RS

-1.0

PromoterAI

0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.45

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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NM_001183.6:c.29T>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over