X-153541364-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001001344.3(ATP2B3):c.214G>A(p.Ala72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,210,608 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A72A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., 21 hem., cov: 24)
  • Exomes 𝑓: 0.00043 (0 hom. 151 hem.)
• Consequence: ATP2B3 NM_001001344.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.74

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032008976).
• BP6: Variant X-153541364-G-A is Benign according to our data. Variant chrX-153541364-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547100.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chrX-153541364-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000497 (56/112624) while in subpopulation AMR AF= 0.00206 (22/10697). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B3	NM_001001344.3	c.214G>A	p.Ala72Thr	missense_variant	4/22	ENST00000263519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B3	ENST00000263519.5	c.214G>A	p.Ala72Thr	missense_variant	4/22	1	NM_001001344.3	P1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 57 AN: 112573 Hom.: 0 Cov.: 24 AF XY: 0.000634 AC XY: 22 AN XY: 34723

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000638

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000404 AC: 74 AN: 183039 Hom.: 0 AF XY: 0.000429 AC XY: 29 AN XY: 67657

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000766

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000576

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000432 AC: 474 AN: 1097984 Hom.: 0 Cov.: 32 AF XY: 0.000415 AC XY: 151 AN XY: 363474

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000597

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000483

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.000497 AC: 56 AN: 112624 Hom.: 0 Cov.: 24 AF XY: 0.000604 AC XY: 21 AN XY: 34784

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000639

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000467 Hom.: 18

Bravo AF: 0.000710

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2022	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.214G>A (p.A72T) alteration is located in exon 2 (coding exon 2) of the ATP2B3 gene. This alteration results from a G to A substitution at nucleotide position 214, causing the alanine (A) at amino acid position 72 to be replaced by a threonine (T). 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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.051	T;.;.;.;T
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.032	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.28	N;N;N;N;N
MutationTaster	Benign	0.88	N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.48	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.0040	B;.;.;B;B
Vest4		0.070
MVP		0.81
MPC		0.57
ClinPred		0.013	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.45

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: rs149114271; hg19: chrX-152806822;