17-3930308-G-A
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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):c.2737C>T(p.Leu913Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,594,268 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 (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
ATP2A3
NM_005173.4 missense
NM_005173.4 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 8.13
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, 0.881
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000184 AC: 4AN: 216814Hom.: 0 AF XY: 0.00000855 AC XY: 1AN XY: 116910
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GnomAD4 exome AF: 0.0000153 AC: 22AN: 1442062Hom.: 0 Cov.: 33 AF XY: 0.0000126 AC XY: 9AN XY: 715422
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74350
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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 | Feb 08, 2023 | The c.2737C>T (p.L913F) alteration is located in exon 18 (coding exon 18) of the ATP2A3 gene. This alteration results from a C to T substitution at nucleotide position 2737, causing the leucine (L) at amino acid position 913 to be replaced by a phenylalanine (F). 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
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
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
Benign
L;L;L;.;L;L;L;.
PrimateAI
Pathogenic
D
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;D;D;.;.;D;D;.
Vest4
MVP
MPC
1.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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