rs34217273

Positions:

• chrX-40591350-G-A
• chrX-40591350-G-C
• chrX-40591350-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005765.3(ATP6AP2):​c.285G>A​(p.Ser95=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,209,308 control chromosomes in the GnomAD database, including 70 homozygotes. There are 1,049 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S95S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (32 hom., 493 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (38 hom. 556 hem.)
• Consequence: ATP6AP2 NM_005765.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.90

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-40591350-G-A is Benign according to our data. Variant chrX-40591350-G-A is described in ClinVar as [Benign]. Clinvar id is 128486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP2	NM_005765.3	c.285G>A	p.Ser95=	synonymous_variant	3/9	ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2	c.285G>A	p.Ser95=	synonymous_variant	3/9	1	NM_005765.3	P3

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 1733 AN: 112095 Hom.: 32 Cov.: 23 AF XY: 0.0141 AC XY: 485 AN XY: 34283

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00826

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000737

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0133

GnomAD3 exomes AF: 0.00489 AC: 896 AN: 183279 Hom.: 19 AF XY: 0.00316 AC XY: 214 AN XY: 67735

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00183 AC: 2011 AN: 1097158 Hom.: 38 Cov.: 30 AF XY: 0.00153 AC XY: 556 AN XY: 362614

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.0155 AC: 1741 AN: 112150 Hom.: 32 Cov.: 23 AF XY: 0.0144 AC XY: 493 AN XY: 34348

Gnomad4 AFR AF: 0.0525

Gnomad4 AMR AF: 0.00815

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000739

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.0131

Alfa AF: 0.00104 Hom.: 4

Bravo AF: 0.0186

EpiCase AF: 0.000382

EpiControl AF: 0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 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

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 27, 2018

- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2014

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.33
DANN	Benign	0.53

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: rs34217273; hg19: chrX-40450602;