X-153541663-G-A

Position:

• chrX-153541663-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001001344.3(ATP2B3):​c.407-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,208,161 control chromosomes in the GnomAD database, including 67 homozygotes. There are 851 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (36 hom., 419 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (31 hom. 432 hem.)
• Consequence: ATP2B3 NM_001001344.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002787
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.699

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-153541663-G-A is Benign according to our data. Variant chrX-153541663-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 711254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153541663-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0147 (1645/111574) while in subpopulation AFR AF= 0.0511 (1568/30659). AF 95% confidence interval is 0.049. There are 36 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B3	NM_001001344.3	c.407-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000263519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B3	ENST00000263519.5	c.407-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001001344.3	P1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1636 AN: 111520 Hom.: 36 Cov.: 23 AF XY: 0.0123 AC XY: 414 AN XY: 33720

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.00437

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000382

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00797

GnomAD3 exomes AF: 0.00415 AC: 755 AN: 182076 Hom.: 14 AF XY: 0.00253 AC XY: 169 AN XY: 66770

Gnomad AFR exome AF: 0.0515

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.00156 AC: 1714 AN: 1096587 Hom.: 31 Cov.: 32 AF XY: 0.00119 AC XY: 432 AN XY: 362259

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00181

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000904

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0147 AC: 1645 AN: 111574 Hom.: 36 Cov.: 23 AF XY: 0.0124 AC XY: 419 AN XY: 33784

Gnomad4 AFR AF: 0.0511

Gnomad4 AMR AF: 0.00446

Gnomad4 ASJ AF: 0.00265

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.00787

Alfa AF: 0.00733 Hom.: 38

Bravo AF: 0.0168

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked progressive cerebellar ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.92
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
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

LitVar

Other links and lift over

dbSNP: rs139607201; hg19: chrX-152807121;