Genetic Variant ATP6AP2:n.-120G>A (chrX-40580946-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000636409.1(ATP6AP2):c.-120G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 897,280 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 61 hemizygotes 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: 𝑓 0.0010 ( 0 hom., 35 hem., cov: 25)

Exomes 𝑓: 0.00013 ( 0 hom. 26 hem. )

Consequence

ATP6AP2
ENST00000636409.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.367

Publications

0 publications found

Variant links:

Genes affected

ATP6AP2 (HGNC:18305): (ATPase H+ transporting accessory protein 2) This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases. [provided by RefSeq, Jul 2008]

ATP6AP2 Gene-Disease associations (from GenCC):

ATP6AP2-related disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
congenital disorder of glycosylation, type IIr
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
syndromic X-linked intellectual disability Hedera type
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
X-linked parkinsonism-spasticity syndrome
Inheritance: Unknown, XL Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp

ATP6AP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BS2

High Hemizygotes in GnomAd4 at 35 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636409.1. 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
	ATP6AP2	NM_005765.3	MANE Select	c.-120G>A		upstream_gene	N/A	NP_005756.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP6AP2	ENST00000636639.1	TSL:1	n.-120G>A	non_coding_transcript_exon	Exon 1 of 10	ENSP00000490382.1	A0A1B0GV60
ATP6AP2	ENST00000636639.1	TSL:1	n.-120G>A	5_prime_UTR	Exon 1 of 10	ENSP00000490382.1	A0A1B0GV60
ATP6AP2	ENST00000901375.1		c.-120G>A	5_prime_UTR	Exon 1 of 8	ENSP00000571434.1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

115

AN:

113246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000184

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:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000279

AC:

AN:

100409

AF XY:

0.000165

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.000414

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

104

AN:

783984

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

216346

show subpopulations

African (AFR)

AF:

0.00338

AC:

AN:

19521

American (AMR)

AF:

0.000365

AC:

AN:

27391

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16825

East Asian (EAS)

AF:

0.00

AC:

AN:

25651

South Asian (SAS)

AF:

0.00

AC:

AN:

44289

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30031

Middle Eastern (MID)

AF:

0.000289

AC:

AN:

3462

European-Non Finnish (NFE)

AF:

0.0000327

AC:

AN:

581206

Other (OTH)

AF:

0.000225

AC:

AN:

35608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00102

AC:

115

AN:

113296

Hom.:

Cov.:

AF XY:

0.000987

AC XY:

AN XY:

35454

show subpopulations

African (AFR)

AF:

0.00358

AC:

112

AN:

31293

American (AMR)

AF:

0.000184

AC:

AN:

10866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53339

Other (OTH)

AF:

0.00

AC:

AN:

1549

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.00103

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.2

(source)

DANN

Benign

0.88

PhyloP100

0.37

PromoterAI

-0.052

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

Publications

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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