X-154428787-T-TGGC

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001183.6(ATP6AP1):c.114_116dup(p.Ala40dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,124,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 5 hem., cov: 21)
  • Exomes 𝑓: 0.00012 (0 hom. 29 hem.)
• Consequence: ATP6AP1 NM_001183.6 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.146

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant X-154428787-T-TGGC is Benign according to our data. Variant chrX-154428787-T-TGGC is described in ClinVar as [Likely_benign]. Clinvar id is 2058049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP1	NM_001183.6	c.114_116dup	p.Ala40dup	inframe_insertion	1/10	ENST00000369762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP1	ENST00000369762.7	c.114_116dup	p.Ala40dup	inframe_insertion	1/10	1	NM_001183.6	P1

Frequencies

GnomAD3 genomes AF: 0.000294 AC: 33 AN: 112150 Hom.: 0 Cov.: 21 AF XY: 0.000145 AC XY: 5 AN XY: 34496

Gnomad AFR AF: 0.000425

Gnomad AMI AF: 0.00880

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000644

Gnomad MID AF: 0.00426

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.000660

GnomAD3 exomes AF: 0.000129 AC: 7 AN: 54469 Hom.: 0 AF XY: 0.0000686 AC XY: 1 AN XY: 14567

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000674

Gnomad NFE exome AF: 0.0000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 126 AN: 1012259 Hom.: 0 Cov.: 31 AF XY: 0.0000890 AC XY: 29 AN XY: 325761

Gnomad4 AFR exome AF: 0.000826

Gnomad4 AMR exome AF: 0.000132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.000294 AC: 33 AN: 112191 Hom.: 0 Cov.: 21 AF XY: 0.000145 AC XY: 5 AN XY: 34547

Gnomad4 AFR AF: 0.000424

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000644

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs781797236; hg19: chrX-153657133;