Genetic Variant ATP2B3:p.Val120Ile (chrX-153541508-G-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.358G>A(p.Val120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,209,957 control chromosomes in the GnomAD database, including 1 homozygotes. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00011 ( 1 hom. 57 hem. )

Consequence

ATP2B3
NM_001001344.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.44

Publications

2 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 (MetaRNN=0.021639466).

BP6

Variant X-153541508-G-A is Benign according to our data. Variant chrX-153541508-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3328779.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000447 (5/111858) while in subpopulation SAS AF = 0.00153 (4/2612). AF 95% confidence interval is 0.000523. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 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	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2B3	NM_001001344.3	MANE Select	c.358G>A	p.Val120Ile	missense	Exon 4 of 22	NP_001001344.1	Q16720-1
ATP2B3	NM_001388362.1		c.358G>A	p.Val120Ile	missense	Exon 4 of 22	NP_001375291.1
ATP2B3	NM_001388361.1		c.358G>A	p.Val120Ile	missense	Exon 3 of 21	NP_001375290.1	Q16720-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2B3	ENST00000263519.5	TSL:1 MANE Select	c.358G>A	p.Val120Ile	missense	Exon 4 of 22	ENSP00000263519.4	Q16720-1
ATP2B3	ENST00000359149.9	TSL:1	c.358G>A	p.Val120Ile	missense	Exon 4 of 23	ENSP00000352062.3	Q16720-2
ATP2B3	ENST00000496610.2	TSL:3	c.358G>A	p.Val120Ile	missense	Exon 4 of 23	ENSP00000516173.1	A0A994J5M1

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111806

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:

0.00

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000137

AC:

AN:

183056

AF XY:

0.000251

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000106

AC:

116

AN:

1098099

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

AN XY:

363517

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30206

South Asian (SAS)

AF:

0.00181

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40410

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

842117

Other (OTH)

AF:

0.000108

AC:

AN:

46090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.0000447

AC:

AN:

111858

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30850

American (AMR)

AF:

0.00

AC:

AN:

10588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00153

AC:

AN:

2612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6107

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53078

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.0000524

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.075

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.23

PhyloP100

2.4

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.030

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.055

Vest4

0.035

MutPred

0.44

Loss of catalytic residue at V120 (P = 0.0205)

MVP

0.60

MPC

0.46

ClinPred

0.075

GERP RS

4.7

Varity_R

0.084

gMVP

0.65

Mutation Taster

=100/0

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