1-203699483-C-T

Position:

• chr1-203699483-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001684.5(ATP2B4):​c.415C>T​(p.Pro139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ATP2B4 NM_001684.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.08

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP2B4
• BP4: Computational evidence support a benign effect (MetaRNN=0.053040802).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B4	NM_001684.5	c.415C>T	p.Pro139Ser	missense_variant	4/21	ENST00000357681.10
ATP2B4	NM_001001396.3	c.415C>T	p.Pro139Ser	missense_variant	4/22
ATP2B4	NM_001365783.2	c.415C>T	p.Pro139Ser	missense_variant	4/21
ATP2B4	NM_001365784.2	c.415C>T	p.Pro139Ser	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10	c.415C>T	p.Pro139Ser	missense_variant	4/21	1	NM_001684.5	A1
ATP2B4	ENST00000341360.7	c.415C>T	p.Pro139Ser	missense_variant	4/22	1		P4
ATP2B4	ENST00000705901.1	c.415C>T	p.Pro139Ser	missense_variant	4/21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251370 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000958 AC: 14 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.415C>T (p.P139S) alteration is located in exon 4 (coding exon 3) of the ATP2B4 gene. This alteration results from a C to T substitution at nucleotide position 415, causing the proline (P) at amino acid position 139 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 12, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ATP2B4-related conditions. This variant is present in population databases (rs758844046, ExAC 0.05%). This sequence change replaces proline with serine at codon 139 of the ATP2B4 protein (p.Pro139Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.1
DANN	Benign	0.69
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.062	N
LIST_S2	Uncertain	0.86	D;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.41	N;N;N
REVEL	Benign	0.076
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.21
MutPred		0.35		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.57
MPC		0.44
ClinPred		0.026	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.44

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: rs758844046; hg19: chr1-203668611;