17-3929420-G-A

Variant names:

• chr17-3929420-G-A
• rs199574831
• NM_005173.4:c.2770C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005173.4(ATP2A3):​c.2770C>T​(p.Arg924Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,593,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.19
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16048807).
• BP6: Variant 17-3929420-G-A is Benign according to our data. Variant chr17-3929420-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 757608.

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.2770C>T	p.Arg924Trp	missense	Exon 19 of 21	NP_005164.2
	ATP2A3	NM_174953.3		c.2770C>T	p.Arg924Trp	missense	Exon 19 of 23	NP_777613.1	Q93084-5
	ATP2A3	NM_174954.3		c.2770C>T	p.Arg924Trp	missense	Exon 19 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.2770C>T	p.Arg924Trp	missense	Exon 19 of 21	ENSP00000380234.3	Q93084-2
	ATP2A3	ENST00000397043.7	TSL:1	c.2770C>T	p.Arg924Trp	missense	Exon 19 of 21	ENSP00000380236.3	Q93084-4
	ATP2A3	ENST00000570845.5	TSL:1	c.97C>T	p.Arg33Trp	missense	Exon 2 of 6	ENSP00000461480.1	A0A0C4DGN3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000240 AC: 51 AN: 212300 AF XY: 0.000165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000924

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.000170 AC: 245 AN: 1441016 Hom.: 0 Cov.: 31 AF XY: 0.000141 AC XY: 101 AN XY: 715132

African (AFR) AF: 0.0000606 AC: 2 AN: 33022

American (AMR) AF: 0.000782 AC: 33 AN: 42174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 38540

South Asian (SAS) AF: 0.00 AC: 0 AN: 83028

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5142

European-Non Finnish (NFE) AF: 0.000183 AC: 202 AN: 1102914

Other (OTH) AF: 0.000118 AC: 7 AN: 59472

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.00170 AC: 26 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68004

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000208 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.96
MPC		1.5
ClinPred		0.53	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.89
Mutation Taster		=38/62	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: rs199574831; hg19: chr17-3832714;