17-3928687-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_005173.4(ATP2A3):āc.2956T>Cā(p.Tyr986His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,551,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.0000036 ( 0 hom. )
Consequence
ATP2A3
NM_005173.4 missense
NM_005173.4 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
ATP2A3 (HGNC:813): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152006Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000357 AC: 5AN: 1399016Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3AN XY: 690084
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152006Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74262
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2023 | The c.2956T>C (p.Y986H) alteration is located in exon 20 (coding exon 20) of the ATP2A3 gene. This alteration results from a T to C substitution at nucleotide position 2956, causing the tyrosine (Y) at amino acid position 986 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.;M;M;M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;.;D;D;D;.
Sift4G
Benign
T;T;T;D;T;T;T;D
Polyphen
D;P;D;.;.;D;D;.
Vest4
MutPred
Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);.;Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);.;
MVP
MPC
4.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at