17-3928687-A-G

Variant names:

• chr17-3928687-A-G
• rs1422022558
• NM_005173.4:c.2956T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005173.4(ATP2A3):​c.2956T>C​(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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A3	NM_005173.4	MANE Select	c.2956T>C	p.Tyr986His	missense	Exon 20 of 21	NP_005164.2
	ATP2A3	NM_174953.3		c.2956T>C	p.Tyr986His	missense	Exon 20 of 23	NP_777613.1	Q93084-5
	ATP2A3	NM_174954.3		c.2956T>C	p.Tyr986His	missense	Exon 20 of 23	NP_777614.1	Q93084-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A3	ENST00000397041.8	TSL:1 MANE Select	c.2956T>C	p.Tyr986His	missense	Exon 20 of 21	ENSP00000380234.3	Q93084-2
	ATP2A3	ENST00000397043.7	TSL:1	c.2956T>C	p.Tyr986His	missense	Exon 20 of 21	ENSP00000380236.3	Q93084-4
	ATP2A3	ENST00000570845.5	TSL:1	c.283T>C	p.Tyr95His	missense	Exon 3 of 6	ENSP00000461480.1	A0A0C4DGN3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399016 Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3 AN XY: 690084

African (AFR) AF: 0.0000633 AC: 2 AN: 31612

American (AMR) AF: 0.00 AC: 0 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35750

South Asian (SAS) AF: 0.00 AC: 0 AN: 79260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079084

Other (OTH) AF: 0.00 AC: 0 AN: 58008

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74262

African (AFR) AF: 0.0000967 AC: 4 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.072	T
Polyphen		0.98	D
Vest4		0.70
MutPred		0.76		Gain of disorder (P = 0.0161)
MVP		0.89
MPC		4.3
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.66
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1422022558; hg19: chr17-3831981;