rs190477001

chrX-40588981-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005765.3(ATP6AP2):c.38-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,206,348 control chromosomes in the GnomAD database, including 1 homozygotes. There are 132 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., 61 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (0 hom. 71 hem.)
• Consequence: ATP6AP2 NM_005765.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001392
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0630

Genes affected

ATP6AP2 (HGNC:18305): (ATPase H+ transporting accessory protein 2) This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-40588981-T-C is Benign according to our data. Variant chrX-40588981-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-40588981-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 61 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP2	NM_005765.3	c.38-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2	c.38-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005765.3	P3

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 256 AN: 111830 Hom.: 1 Cov.: 23 AF XY: 0.00179 AC XY: 61 AN XY: 33996

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000479

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: 0.00

Gnomad OTH AF: 0.00267

GnomAD3 exomes AF: 0.000633 AC: 116 AN: 183129 Hom.: 0 AF XY: 0.000399 AC XY: 27 AN XY: 67673

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 264 AN: 1094464 Hom.: 0 Cov.: 29 AF XY: 0.000197 AC XY: 71 AN XY: 360390

Gnomad4 AFR exome AF: 0.00802

Gnomad4 AMR exome AF: 0.000540

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000477

Gnomad4 OTH exome AF: 0.000610

GnomAD4 genome AF: 0.00229 AC: 256 AN: 111884 Hom.: 1 Cov.: 23 AF XY: 0.00179 AC XY: 61 AN XY: 34060

Gnomad4 AFR AF: 0.00802

Gnomad4 AMR AF: 0.000478

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00264

Alfa AF: 0.00169 Hom.: 10

Bravo AF: 0.00289

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Syndromic X-linked intellectual disability Hedera type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Syndromic X-linked intellectual disability Hedera type;C3806722:X-linked parkinsonism-spasticity syndrome;C5393313:Congenital disorder of glycosylation, type IIr Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

ATP6AP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2019

This variant is classified as 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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	10
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.010
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: rs190477001; hg19: chrX-40448233;