Genetic Variant ATP2B3:c.208+7C>A (chrX-153536462-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001001344.3(ATP2B3):c.208+7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000937 in 1,185,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 1 hem., cov: 26)

Exomes 𝑓: 0.000094 ( 0 hom. 32 hem. )

Consequence

ATP2B3
NM_001001344.3 splice_region, intron

Scores

Splicing: ADA: 0.00009711

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.181

Publications

0 publications found

Variant links:

Genes affected

ATP2B3 (HGNC:816): (ATPase plasma membrane Ca2+ transporting 3) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 3. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B3 Gene-Disease associations (from GenCC):

X-linked progressive cerebellar ataxia
Inheritance: Unknown, XL Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
X-linked non progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ATP2B3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant X-153536462-C-A is Benign according to our data. Variant chrX-153536462-C-A is described in ClinVar as Benign. ClinVar VariationId is 727955.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000885 (10/112948) while in subpopulation AMR AF = 0.000835 (9/10772). AF 95% confidence interval is 0.000435. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 32 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001344.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP2B3	NM_001001344.3	MANE Select	c.208+7C>A	splice_region intron	N/A	NP_001001344.1	Q16720-1
ATP2B3	NM_001388362.1		c.208+7C>A	splice_region intron	N/A	NP_001375291.1
ATP2B3	NM_001388361.1		c.208+7C>A	splice_region intron	N/A	NP_001375290.1	Q16720-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP2B3	ENST00000263519.5	TSL:1 MANE Select	c.208+7C>A	splice_region intron	N/A	ENSP00000263519.4	Q16720-1
ATP2B3	ENST00000359149.9	TSL:1	c.208+7C>A	splice_region intron	N/A	ENSP00000352062.3	Q16720-2
ATP2B3	ENST00000496610.2	TSL:3	c.208+7C>A	splice_region intron	N/A	ENSP00000516173.1	A0A994J5M1

Frequencies

GnomAD3 genomes

AF:

0.0000885

AC:

AN:

112948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000835

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000654

AC:

AN:

137614

AF XY:

0.000573

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00395

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:

0.000820

GnomAD4 exome

AF:

0.0000942

AC:

101

AN:

1072151

Hom.:

Cov.:

AF XY:

0.0000920

AC XY:

AN XY:

347791

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26118

American (AMR)

AF:

0.00319

AC:

AN:

30744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18851

East Asian (EAS)

AF:

0.00

AC:

AN:

29314

South Asian (SAS)

AF:

0.00

AC:

AN:

50971

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38465

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2930

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829655

Other (OTH)

AF:

0.0000665

AC:

AN:

45103

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000885

AC:

AN:

112948

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35090

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31133

American (AMR)

AF:

0.000835

AC:

AN:

10772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2771

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53324

Other (OTH)

AF:

0.00

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

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:

0.00

Hom.:

Bravo

AF:

0.000264

ClinVar

ClinVar submissions

Significance:Benign

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

BayesDel_noAF

Benign

-0.73

CADD

Benign

4.4

(source)

DANN

Benign

0.60

PhyloP100

-0.18

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000097

dbscSNV1_RF

Benign

0.0020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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