chr17-3935209-T-G

Variant names:

• chr17-3935209-T-G
• rs761563353
• NM_005173.4:c.2593A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005173.4(ATP2A3):​c.2593A>C​(p.Ile865Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.738

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066278666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A3	NM_005173.4	c.2593A>C	p.Ile865Leu	missense_variant	Exon 17 of 21	ENST00000397041.8	NP_005164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A3	ENST00000397041.8	c.2593A>C	p.Ile865Leu	missense_variant	Exon 17 of 21	1	NM_005173.4	ENSP00000380234.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250954 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135816

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461730 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	8.1
DANN	Benign	0.90
DEOGEN2	Benign	0.39	.;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.78	T;T;.;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.066	T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.79	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.22	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.64	T;T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B
Vest4		0.23
MutPred		0.61		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.22
MPC		0.53
ClinPred		0.056	T
GERP RS		-2.9
Varity_R		0.035
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs761563353; hg19: chr17-3838503;