Genetic Variant ATP6AP1:p.Ala37_Ala39del (chrX-154428787-TGGCGGCGGC-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001183.6(ATP6AP1):c.108_116delGGCGGCGGC(p.Ala37_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 0.00000978 in 1,124,743 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000089 ( 0 hom. 3 hem. )

Consequence

ATP6AP1
NM_001183.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.270

Publications

3 publications found

Variant links:

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 links:

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

ATP6AP1-DT links:

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ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in NM_001183.6

BS2

High Hemizygotes in GnomAdExome4 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.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	Exon 1 of 10	NP_001174.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP6AP1	ENST00000369762.7	TSL:1 MANE Select	c.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000358777.2	Q15904
ATP6AP1	ENST00000945275.1		c.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	Exon 1 of 11	ENSP00000615334.1
ATP6AP1	ENST00000862438.1		c.108_116delGGCGGCGGC	p.Ala37_Ala39del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000532497.1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112151

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1012551

Hom.:

AF XY:

0.00000920

AC XY:

AN XY:

325977

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

20805

American (AMR)

AF:

0.00

AC:

AN:

22652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16951

East Asian (EAS)

AF:

0.000124

AC:

AN:

24117

South Asian (SAS)

AF:

0.00

AC:

AN:

46151

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28515

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3624

European-Non Finnish (NFE)

AF:

0.00000620

AC:

AN:

806972

Other (OTH)

AF:

0.00

AC:

AN:

42764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34548

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30645

American (AMR)

AF:

0.00

AC:

AN:

10797

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.000282

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2811

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6209

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53116

Other (OTH)

AF:

0.00

AC:

AN:

1534

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.27

Splicing

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

Publications

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X-154428787-TGGCGGCGGCGGC-TGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over