chrX-154428705-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001183.6(ATP6AP1):c.13A>G(p.Met5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000783 in 1,149,523 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 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., 1 hem., cov: 25)

Exomes 𝑓: 0.0000068 ( 0 hom. 3 hem. )

Consequence

ATP6AP1
NM_001183.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.133

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052995026).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP1	NM_001183.6 link	c.13A>G	p.Met5Val	missense_variant	Exon 1 of 10	ENST00000369762.7	NP_001174.2
ATP6AP1-DT	NR_103768.1 link	n.-226T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7 link	c.13A>G	p.Met5Val	missense_variant	Exon 1 of 10	1	NM_001183.6	ENSP00000358777.2		Q15904

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113647

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:

0.0000374

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000676

AC:

AN:

1035876

Hom.:

Cov.:

AF XY:

0.00000891

AC XY:

AN XY:

336590

show subpopulations

African (AFR)

AF:

0.0000441

AC:

AN:

22685

American (AMR)

AF:

0.0000736

AC:

AN:

27192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18213

East Asian (EAS)

AF:

0.00

AC:

AN:

25380

South Asian (SAS)

AF:

0.00

AC:

AN:

49296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30063

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3996

European-Non Finnish (NFE)

AF:

0.00000491

AC:

AN:

815207

Other (OTH)

AF:

0.00

AC:

AN:

43844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000176

AC:

AN:

113647

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

35783

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31356

American (AMR)

AF:

0.00

AC:

AN:

10886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3607

South Asian (SAS)

AF:

0.00

AC:

AN:

2864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000374

AC:

AN:

53434

Other (OTH)

AF:

0.00

AC:

AN:

1537

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:

0.000214

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the ATP6AP1 protein (p.Met5Val). This variant has not been reported in the literature in individuals affected with ATP6AP1-related conditions. 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. 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.5

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.037

T;T;T

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.38

T;T;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.13

PrimateAI

Benign

0.44

PROVEAN

Benign

0.0

N;N;N

REVEL

Benign

0.018

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.11

MutPred

0.34

Gain of catalytic residue at M5 (P = 0.0248);Gain of catalytic residue at M5 (P = 0.0248);Gain of catalytic residue at M5 (P = 0.0248);

MVP

0.15

MPC

0.27

ClinPred

0.029

GERP RS

1.7

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.089

gMVP

0.26

Mutation Taster

=99/1

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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chrX-154428705-A-G

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