rs16927997

Positions:

• chr9-125236118-A-G

Variant summary

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

The ENST00000324460.7(HSPA5):​c.*474T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 152,912 control chromosomes in the GnomAD database, including 103 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 0.013 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: HSPA5 ENST00000324460.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200

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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA5	NM_005347.5	c.*474T>C		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.*474T>C		3_prime_UTR_variant	8/8	1	NM_005347.5	ENSP00000324173	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1948 AN: 151814 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0808

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0836

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00102 AC: 1 AN: 980 Hom.: 0 Cov.: 0 AF XY: 0.00193 AC XY: 1 AN XY: 518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0625

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0128 AC: 1949 AN: 151932 Hom.: 103 Cov.: 32 AF XY: 0.0143 AC XY: 1064 AN XY: 74252

Gnomad4 AFR AF: 0.00309

Gnomad4 AMR AF: 0.0810

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0836

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0000951

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00558 Hom.: 6

Bravo AF: 0.0196

Asia WGS AF: 0.0500 AC: 172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.7
DANN	Benign	0.65

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: rs16927997; hg19: chr9-127998397;