X-154428787-TGGCGGCGGCGGC-TGGCGGCGGC

Variant names:

• chrX-154428787-TGGC-T
• rs781797236
• NM_001183.6:c.114_116delGGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001183.6(ATP6AP1):​c.114_116delGGC​(p.Ala39del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,121,018 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 54 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A38A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.00031 (0 hom. 51 hem.)
• Consequence: ATP6AP1 NM_001183.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 0.146
• Publications: 3 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001183.6
• BS2: High Hemizygotes in GnomAd4 at 3 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001183.6. 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
	ATP6AP1	NM_001183.6	MANE Select	c.114_116delGGC	p.Ala39del	disruptive_inframe_deletion	Exon 1 of 10	NP_001174.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	ENST00000369762.7	TSL:1 MANE Select	c.114_116delGGC	p.Ala39del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000358777.2	Q15904
	ATP6AP1	ENST00000945275.1		c.114_116delGGC	p.Ala39del	disruptive_inframe_deletion	Exon 1 of 11	ENSP00000615334.1
	ATP6AP1	ENST00000862438.1		c.114_116delGGC	p.Ala39del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000532497.1

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 112146 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000226

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00252 AC: 137 AN: 54469 AF XY: 0.000137

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.00302

Gnomad ASJ exome AF: 0.00197

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00225

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00241

GnomAD4 exome AF: 0.000312 AC: 315 AN: 1008872 Hom.: 0 AF XY: 0.000157 AC XY: 51 AN XY: 324024

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

African (AFR) AF: 0.000241 AC: 5 AN: 20756

American (AMR) AF: 0.00166 AC: 37 AN: 22265

Ashkenazi Jewish (ASJ) AF: 0.000356 AC: 6 AN: 16847

East Asian (EAS) AF: 0.000250 AC: 6 AN: 24003

South Asian (SAS) AF: 0.000438 AC: 20 AN: 45644

European-Finnish (FIN) AF: 0.000388 AC: 11 AN: 28351

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3613

European-Non Finnish (NFE) AF: 0.000270 AC: 217 AN: 804796

Other (OTH) AF: 0.000305 AC: 13 AN: 42597

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000116 AC: 13 AN: 112146 Hom.: 0 Cov.: 21 AF XY: 0.0000870 AC XY: 3 AN XY: 34492

African (AFR) AF: 0.0000327 AC: 1 AN: 30584

American (AMR) AF: 0.00 AC: 0 AN: 10784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2821

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53120

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00232 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	ATP6AP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=95/5	polymorphism

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: rs781797236; hg19: chrX-153657133; COSMIC: COSV100645207; COSMIC: COSV100645207;