9-125238840-C-T

Position:

• chr9-125238840-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000324460.7(HSPA5):​c.997-13G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.079 in 1,612,266 control chromosomes in the GnomAD database, including 6,043 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1139 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4904 hom.)
• Consequence: HSPA5 ENST00000324460.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

Genes affected

HSPA5 (HGNC:5238): (heat shock protein family A (Hsp70) member 5) The protein encoded by this gene is a member of the heat shock protein 70 (HSP70) family. This protein localizes to the lumen of the endoplasmic reticulum (ER) where it operates as a typical HSP70 chaperone involved in the folding and assembly of proteins in the ER and is a master regulator of ER homeostasis. During cellular stress, as during viral infection or tumorogenesis, this protein interacts with the transmembrane stress sensor proteins PERK (protein kinase R-like endoplasmic reticulum kinase), IRE1 (inositol-requiring kinase 1), and ATF6 (activating transcription factor 6) where it acts as a repressor of the unfolded protein response (UPR) and also plays a role in cellular apoptosis and senescence. Elevated expression and atypical translocation of this protein to the cell surface has been reported in viral infections and some types of cancer cells. At the cell surface this protein may facilitate viral attachment and entry to host cells. This gene is a therapeutic target for the treatment of coronavirus diseases and chemoresistant cancers. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA5	NM_005347.5	c.997-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000324460.7	NP_005338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA5	ENST00000324460.7	c.997-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005347.5	ENSP00000324173	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16735 AN: 151970 Hom.: 1139 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0610

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0970

GnomAD3 exomes AF: 0.0909 AC: 22788 AN: 250818 Hom.: 1305 AF XY: 0.0908 AC XY: 12330 AN XY: 135736

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0396

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0934

Gnomad NFE exome AF: 0.0737

Gnomad OTH exome AF: 0.0878

GnomAD4 exome AF: 0.0757 AC: 110574 AN: 1460178 Hom.: 4904 Cov.: 31 AF XY: 0.0771 AC XY: 56013 AN XY: 726390

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0421

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0932

Gnomad4 NFE exome AF: 0.0665

Gnomad4 OTH exome AF: 0.0872

GnomAD4 genome AF: 0.110 AC: 16763 AN: 152088 Hom.: 1139 Cov.: 32 AF XY: 0.112 AC XY: 8321 AN XY: 74354

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0607

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0974

Gnomad4 NFE AF: 0.0711

Gnomad4 OTH AF: 0.0951

Alfa AF: 0.0841 Hom.: 359

Bravo AF: 0.111

Asia WGS AF: 0.134 AC: 464 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs430397; hg19: chr9-128001119;