X-154428735-C-T

Position:

• chrX-154428735-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001183.6(ATP6AP1):​c.43C>T​(p.Arg15Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,147,136 control chromosomes in the GnomAD database, including 4 homozygotes. There are 381 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R15R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., 17 hem., cov: 25)
  • Exomes 𝑓: 0.00096 (3 hom. 364 hem.)
• Consequence: ATP6AP1 NM_001183.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.111

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065576136).
• BP6: Variant X-154428735-C-T is Benign according to our data. Variant chrX-154428735-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 595205.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP1	NM_001183.6	c.43C>T	p.Arg15Trp	missense_variant	1/10	ENST00000369762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP1	ENST00000369762.7	c.43C>T	p.Arg15Trp	missense_variant	1/10	1	NM_001183.6	P1

Frequencies

GnomAD3 genomes AF: 0.000705 AC: 80 AN: 113468 Hom.: 1 Cov.: 25 AF XY: 0.000477 AC XY: 17 AN XY: 35608

Gnomad AFR AF: 0.0000639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000276

Gnomad ASJ AF: 0.00150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00349

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00120 AC: 101 AN: 84020 Hom.: 1 AF XY: 0.00182 AC XY: 48 AN XY: 26346

Gnomad AFR exome AF: 0.000349

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00316

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00342

Gnomad FIN exome AF: 0.000485

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000963 AC: 995 AN: 1033620 Hom.: 3 Cov.: 31 AF XY: 0.00109 AC XY: 364 AN XY: 335224

Gnomad4 AFR exome AF: 0.0000446

Gnomad4 AMR exome AF: 0.0000375

Gnomad4 ASJ exome AF: 0.00282

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00388

Gnomad4 FIN exome AF: 0.000266

Gnomad4 NFE exome AF: 0.000846

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000705 AC: 80 AN: 113516 Hom.: 1 Cov.: 25 AF XY: 0.000477 AC XY: 17 AN XY: 35666

Gnomad4 AFR AF: 0.0000638

Gnomad4 AMR AF: 0.000276

Gnomad4 ASJ AF: 0.00150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00350

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00114

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00125 Hom.: 14

Bravo AF: 0.000627

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000965 AC: 5

ExAC AF: 0.00102 AC: 47

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2017	- -

ATP6AP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0066	T;T;T
MutationTaster	Benign	1.0	A
PROVEAN	Benign	-1.2	N;N;N
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Vest4		0.12
MVP		0.13
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.051
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs201620814; hg19: chrX-153657081;