X-40580818-A-T

Variant names:

• chrX-40580818-A-T
• rs191737410
• ENST00000436783.6:c.-111+1071A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000436783.6(ATP6AP2):​c.-111+1071A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 455,715 control chromosomes in the GnomAD database, including 7 homozygotes. There are 283 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., 208 hem., cov: 24)
  • Exomes 𝑓: 0.0010 (0 hom. 75 hem.)
• Consequence: ATP6AP2 ENST00000436783.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.17
• Publications: 0 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: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Hedera type

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

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-40580818-A-T is Benign according to our data. Variant chrX-40580818-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 677651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00665 (746/112210) while in subpopulation AFR AF = 0.0228 (705/30914). AF 95% confidence interval is 0.0214. There are 7 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000436783.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.-248A>T		upstream_gene	N/A	NP_005756.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000436783.6	TSL:5	c.-111+1071A>T		intron	N/A	ENSP00000403969.2	H7C240
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.-248A>T		upstream_gene	N/A	ENSP00000490083.1	O75787-1
	ATP6AP2	ENST00000636639.1	TSL:1	n.-248A>T		upstream_gene	N/A	ENSP00000490382.1	A0A1B0GV60

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 746 AN: 112156 Hom.: 7 Cov.: 24

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000363

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000943

Gnomad OTH AF: 0.00398

GnomAD4 exome AF: 0.00101 AC: 348 AN: 343505 Hom.: 0 AF XY: 0.000661 AC XY: 75 AN XY: 113491

African (AFR) AF: 0.0219 AC: 237 AN: 10844

American (AMR) AF: 0.00241 AC: 57 AN: 23646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11457

East Asian (EAS) AF: 0.00 AC: 0 AN: 21327

South Asian (SAS) AF: 0.00 AC: 0 AN: 32686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22227

Middle Eastern (MID) AF: 0.000554 AC: 1 AN: 1804

European-Non Finnish (NFE) AF: 0.0000150 AC: 3 AN: 199581

Other (OTH) AF: 0.00251 AC: 50 AN: 19933

GnomAD4 genome AF: 0.00665 AC: 746 AN: 112210 Hom.: 7 Cov.: 24 AF XY: 0.00603 AC XY: 208 AN XY: 34488

African (AFR) AF: 0.0228 AC: 705 AN: 30914

American (AMR) AF: 0.00270 AC: 29 AN: 10741

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.000364 AC: 1 AN: 2750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6149

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000943 AC: 5 AN: 53039

Other (OTH) AF: 0.00393 AC: 6 AN: 1528

Alfa AF: 0.00512 Hom.: 15

Bravo AF: 0.00789

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.51
PhyloP100		-1.2
PromoterAI		0.024	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs191737410; hg19: chrX-40440070;