Genetic Variant NM_001183.6:c.65G>A (chrX-154428757-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001183.6(ATP6AP1):c.65G>A(p.Arg22His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000978 in 1,022,443 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.8e-7 ( 0 hom. 0 hem. )

Consequence

ATP6AP1
NM_001183.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.146

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:

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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=0.07970601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP1	NM_001183.6 link	c.65G>A	p.Arg22His	missense_variant	Exon 1 of 10	ENST00000369762.7	NP_001174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7 link	c.65G>A	p.Arg22His	missense_variant	Exon 1 of 10	1	NM_001183.6	ENSP00000358777.2		Q15904

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

72492

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.78e-7

AC:

AN:

1022443

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

330047

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21473

American (AMR)

AF:

0.00

AC:

AN:

23948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17515

East Asian (EAS)

AF:

0.00

AC:

AN:

24458

South Asian (SAS)

AF:

0.00

AC:

AN:

47540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29571

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3846

European-Non Finnish (NFE)

AF:

0.00000123

AC:

AN:

810907

Other (OTH)

AF:

0.00

AC:

AN:

43185

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

5.0

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

T;T;T

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.

PhyloP100

-0.15

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.015

Sift

Benign

0.13

T;T;T

Sift4G

Uncertain

0.031

D;D;T

Polyphen

0.43

B;.;.

Vest4

0.084

MutPred

0.29

Loss of MoRF binding (P = 0.0128);Loss of MoRF binding (P = 0.0128);Loss of MoRF binding (P = 0.0128);

MVP

0.14

MPC

0.33

ClinPred

0.072

GERP RS

-1.6

PromoterAI

-0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.15

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over