Genetic Variant ATP6AP1:p.Ala39dup (chrX-154428787-T-TGGC) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_001183.6(ATP6AP1):c.114_116dupGGC(p.Ala39dup) variant causes a disruptive 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 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.146

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001183.6

BP6

Variant X-154428787-T-TGGC is Benign according to our data. Variant chrX-154428787-T-TGGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2058049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 5 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_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	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.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000358777.2	Q15904
ATP6AP1	ENST00000945275.1		c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000615334.1
ATP6AP1	ENST00000862438.1		c.114_116dupGGC	p.Ala39dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000532497.1

Frequencies

GnomAD3 genomes

AF:

0.000294

AC:

AN:

112150

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000129

AC:

AN:

54469

AF XY:

0.0000686

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

325761

show subpopulations

African (AFR)

AF:

0.000826

AC:

AN:

20581

American (AMR)

AF:

0.000132

AC:

AN:

22644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16951

East Asian (EAS)

AF:

0.00

AC:

AN:

24117

South Asian (SAS)

AF:

0.000130

AC:

AN:

46150

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

28515

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3621

European-Non Finnish (NFE)

AF:

0.0000719

AC:

AN:

806956

Other (OTH)

AF:

0.000234

AC:

AN:

42724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000294

AC:

AN:

112191

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34547

show subpopulations

African (AFR)

AF:

0.000424

AC:

AN:

30644

American (AMR)

AF:

0.00

AC:

AN:

10797

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2811

European-Finnish (FIN)

AF:

0.000644

AC:

AN:

6209

Middle Eastern (MID)

AF:

0.00467

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

53116

Other (OTH)

AF:

0.000652

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000386

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.15

Splicing

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

Publications

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X-154428787-TGGCGGCGGCGGC-TGGCGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over