X-154428498-T-A

Variant names:

• chrX-154428498-T-A
• rs189401774
• ENST00000360656.5:n.52A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000360656.5(ATP6AP1-DT):​n.52A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 407,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000025 (0 hom. 0 hem.)
• Consequence: ATP6AP1-DT ENST00000360656.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810
• Publications: 1 publications found

Genes affected

ATP6AP1-DT (HGNC:25138): (ATP6AP1 divergent transcript)

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]

ATP6AP1 Gene-Disease associations (from GenCC):

• immunodeficiency 47

  Inheritance: XL, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital disorder of glycosylation type II

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP1	NM_001183.6	c.-195T>A		upstream_gene_variant		ENST00000369762.7	NP_001174.2
ATP6AP1-DT	NR_103768.1	n.-19A>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7	c.-195T>A		upstream_gene_variant		1	NM_001183.6	ENSP00000358777.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000245 AC: 1 AN: 407769 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 115069

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8320

American (AMR) AF: 0.00 AC: 0 AN: 8087

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9228

East Asian (EAS) AF: 0.00 AC: 0 AN: 18591

South Asian (SAS) AF: 0.00 AC: 0 AN: 24419

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22073

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1445

European-Non Finnish (NFE) AF: 0.00000340 AC: 1 AN: 294012

Other (OTH) AF: 0.00 AC: 0 AN: 21594

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.3
DANN	Benign	0.44
PhyloP100		0.081
PromoterAI		0.044	Neutral

Splicing

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

Other links and lift over

dbSNP: rs189401774; hg19: chrX-153656844;