1-203698294-A-T

Variant names:

• chr1-203698294-A-T
• rs1193780118
• NM_001684.5:c.331A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001684.5(ATP2B4):​c.331A>T​(p.Ile111Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 152,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: ATP2B4 NM_001684.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B4	NM_001684.5	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 21	ENST00000357681.10	NP_001675.3
ATP2B4	NM_001001396.3	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 22		NP_001001396.1
ATP2B4	NM_001365783.2	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 21		NP_001352712.1
ATP2B4	NM_001365784.2	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 21		NP_001352713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B4	ENST00000357681.10	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 21	1	NM_001684.5	ENSP00000350310.5
ATP2B4	ENST00000341360.7	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 22	1		ENSP00000340930.2
ATP2B4	ENST00000705901.1	c.331A>T	p.Ile111Phe	missense_variant	Exon 3 of 21			ENSP00000516177.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331A>T (p.I111F) alteration is located in exon 3 (coding exon 2) of the ATP2B4 gene. This alteration results from a A to T substitution at nucleotide position 331, causing the isoleucine (I) at amino acid position 111 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.88	P;.;.
Vest4		0.65
MutPred		0.52		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.61
MPC		1.6
ClinPred		0.98	D
GERP RS		5.0
gMVP		0.84

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: rs1193780118; hg19: chr1-203667422;