rs34217273

Variant names:

• chrX-40591350-G-A
• rs34217273
• NM_005765.3:c.285G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000636580.2(ATP6AP2):​c.285G>A​(p.Ser95Ser) 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 ENST00000636580.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.90
• Publications: 2 publications found

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]

ATP6AP2 Gene-Disease associations (from GenCC):

• ATP6AP2-related disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital disorder of glycosylation, type IIr

  Inheritance: AR, XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Hedera type

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked parkinsonism-spasticity syndrome

  Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.046).
• BP6: Variant X-40591350-G-A is Benign according to our data. Variant chrX-40591350-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636580.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.285G>A	p.Ser95Ser	synonymous	Exon 3 of 9	NP_005756.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.285G>A	p.Ser95Ser	synonymous	Exon 3 of 9	ENSP00000490083.1
	ATP6AP2	ENST00000636639.1	TSL:1	n.285G>A		non_coding_transcript_exon	Exon 3 of 10	ENSP00000490382.1
	ATP6AP2	ENST00000378438.9	TSL:5	c.285G>A	p.Ser95Ser	synonymous	Exon 3 of 9	ENSP00000367697.5

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 1733 AN: 112095 Hom.: 32 Cov.: 23

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

GnomAD2 exomes AF: 0.00489 AC: 896 AN: 183279 AF XY: 0.00316

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 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

African (AFR) AF: 0.0579 AC: 1528 AN: 26368

American (AMR) AF: 0.00378 AC: 133 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.000129 AC: 7 AN: 54097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00762 AC: 30 AN: 3937

European-Non Finnish (NFE) AF: 0.000144 AC: 121 AN: 841452

Other (OTH) AF: 0.00417 AC: 192 AN: 46039

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

African (AFR) AF: 0.0525 AC: 1620 AN: 30875

American (AMR) AF: 0.00815 AC: 86 AN: 10551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3594

South Asian (SAS) AF: 0.000739 AC: 2 AN: 2705

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6072

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53265

Other (OTH) AF: 0.0131 AC: 20 AN: 1525

Alfa AF: 0.00104 Hom.: 4

Bravo AF: 0.0186

EpiCase AF: 0.000382

EpiControl AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Syndromic X-linked intellectual disability Hedera type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.33
DANN	Benign	0.53
PhyloP100		-2.9
PromoterAI		-0.041	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34217273; hg19: chrX-40450602;