rs12009

Positions:

• chr9-125235024-G-A
• chr9-125235024-G-T

Variant summary

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

The NM_005347.5(HSPA5):​c.*1568C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 151,706 control chromosomes in the GnomAD database, including 22,443 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 0.54 (22441 hom., cov: 29)
  • Exomes 𝑓: 0.38 (2 hom.)
• Consequence: HSPA5 NM_005347.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA5	NM_005347.5	c.*1568C>T		3_prime_UTR_variant	8/8	ENST00000324460.7	NP_005338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA5	ENST00000324460.7	c.*1568C>T		3_prime_UTR_variant	8/8	1	NM_005347.5	ENSP00000324173	P1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81832 AN: 151572 Hom.: 22426 Cov.: 29

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.375 AC: 6 AN: 16 Hom.: 2 Cov.: 0 AF XY: 0.333 AC XY: 4 AN XY: 12

Gnomad4 NFE exome AF: 0.429

GnomAD4 genome AF: 0.540 AC: 81882 AN: 151690 Hom.: 22441 Cov.: 29 AF XY: 0.546 AC XY: 40471 AN XY: 74130

Gnomad4 AFR AF: 0.481

Gnomad4 AMR AF: 0.635

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.548

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.659

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.551

Alfa AF: 0.530 Hom.: 21396

Bravo AF: 0.536

Asia WGS AF: 0.541 AC: 1882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.63

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: rs12009; hg19: chr9-127997303;