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).

• 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=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6AP1	NM_001183.6	c.43C>T	p.Arg15Trp	missense_variant	1/10	ENST00000369762.7	NP_001174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7	c.43C>T	p.Arg15Trp	missense_variant	1/10	1	NM_001183.6	ENSP00000358777	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	Labcorp Genetics (formerly Invitae), Labcorp	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, no assertion criteria provided

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;