rs3753036

Positions:

• chr1-203708122-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001684.5(ATP2B4):​c.1557+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,430 control chromosomes in the GnomAD database, including 26,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1717 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25052 hom.)
• Consequence: ATP2B4 NM_001684.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0250

Genes affected

ATP2B4 (HGNC:817): (ATPase plasma membrane Ca2+ transporting 4) 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 4. 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=-0.82).
• BP6: Variant 1-203708122-G-A is Benign according to our data. Variant chr1-203708122-G-A is described in ClinVar as [Benign]. Clinvar id is 1578067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2B4	NM_001684.5	c.1557+18G>A		intron_variant		ENST00000357681.10	NP_001675.3
ATP2B4	NM_001001396.3	c.1557+18G>A		intron_variant			NP_001001396.1
ATP2B4	NM_001365783.2	c.1557+18G>A		intron_variant			NP_001352712.1
ATP2B4	NM_001365784.2	c.1557+18G>A		intron_variant			NP_001352713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2B4	ENST00000357681.10	c.1557+18G>A		intron_variant		1	NM_001684.5	ENSP00000350310	A1
ATP2B4	ENST00000341360.7	c.1557+18G>A		intron_variant		1		ENSP00000340930	P4
ATP2B4	ENST00000705901.1	c.1521+18G>A		intron_variant				ENSP00000516177

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20677 AN: 152008 Hom.: 1724 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.164 AC: 41223 AN: 250900 Hom.: 3833 AF XY: 0.173 AC XY: 23499 AN XY: 135636

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.0970

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.217

Gnomad SAS exome AF: 0.245

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.181 AC: 264025 AN: 1461304 Hom.: 25052 Cov.: 33 AF XY: 0.183 AC XY: 133283 AN XY: 726884

Gnomad4 AFR exome AF: 0.0366

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.136 AC: 20664 AN: 152126 Hom.: 1717 Cov.: 32 AF XY: 0.136 AC XY: 10121 AN XY: 74350

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.151

Alfa AF: 0.173 Hom.: 1263

Bravo AF: 0.132

Asia WGS AF: 0.198 AC: 688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.1
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs3753036; hg19: chr1-203677250; COSMIC: COSV58174385;