Genetic Variant ATP2A3:p.Val916Leu (chr17-3929444-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005173.4(ATP2A3):c.2746G>C(p.Val916Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V916I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP2A3
NM_005173.4 missense, splice_region

Scores

Splicing: ADA: 0.0001009

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.510

Publications

1 publications found

Variant links:

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]

ATP2A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.110394925).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005173.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2A3	NM_005173.4	MANE Select	c.2746G>C	p.Val916Leu	missense splice_region	Exon 19 of 21	NP_005164.2
ATP2A3	NM_174953.3		c.2746G>C	p.Val916Leu	missense splice_region	Exon 19 of 23	NP_777613.1	Q93084-5
ATP2A3	NM_174954.3		c.2746G>C	p.Val916Leu	missense splice_region	Exon 19 of 23	NP_777614.1	Q93084-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2A3	ENST00000397041.8	TSL:1 MANE Select	c.2746G>C	p.Val916Leu	missense splice_region	Exon 19 of 21	ENSP00000380234.3	Q93084-2
ATP2A3	ENST00000397043.7	TSL:1	c.2746G>C	p.Val916Leu	missense splice_region	Exon 19 of 21	ENSP00000380236.3	Q93084-4
ATP2A3	ENST00000570845.5	TSL:1	c.73G>C	p.Val25Leu	missense splice_region	Exon 2 of 6	ENSP00000461480.1	A0A0C4DGN3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

206752

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.0045

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.42

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.79

M_CAP

Benign

0.058

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.35

MutationAssessor

Benign

-1.7

PhyloP100

0.51

PrimateAI

Uncertain

0.66

PROVEAN

Benign

1.3

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.25

MutPred

0.55

Gain of helix (P = 0.132)

MVP

0.61

MPC

0.53

ClinPred

0.064

GERP RS

2.7

Varity_R

0.042

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.062

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over