Genetic Variant ATP2A3:p.Val916Phe (chr17-3929444-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005173.4(ATP2A3):c.2746G>T(p.Val916Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,572 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ATP2A3
NM_005173.4 missense, splice_region

Scores

Splicing: ADA: 0.0001139

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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>T	p.Val916Phe	missense splice_region	Exon 19 of 21	NP_005164.2
ATP2A3	NM_174953.3		c.2746G>T	p.Val916Phe	missense splice_region	Exon 19 of 23	NP_777613.1	Q93084-5
ATP2A3	NM_174954.3		c.2746G>T	p.Val916Phe	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>T	p.Val916Phe	missense splice_region	Exon 19 of 21	ENSP00000380234.3	Q93084-2
ATP2A3	ENST00000397043.7	TSL:1	c.2746G>T	p.Val916Phe	missense splice_region	Exon 19 of 21	ENSP00000380236.3	Q93084-4
ATP2A3	ENST00000570845.5	TSL:1	c.73G>T	p.Val25Phe	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

AF:

6.95e-7

AC:

AN:

1438572

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32958

American (AMR)

AF:

0.00

AC:

AN:

41840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25568

East Asian (EAS)

AF:

0.00

AC:

AN:

38496

South Asian (SAS)

AF:

0.00

AC:

AN:

82790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4794

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101838

Other (OTH)

AF:

0.00

AC:

AN:

59366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.66

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.4

PhyloP100

0.51

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

0.70

Vest4

0.67

MutPred

0.60

Loss of helix (P = 0.1706)

MVP

0.90

MPC

1.4

ClinPred

0.97

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.42

gMVP

0.79

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over