9-125241509-GCC-GCCC

Variant names:

• chr9-125241509-G-GC
• rs3216733
• NM_005347.5:c.-384_-383insG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005347.5(HSPA5):​c.-384_-383insG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0072 (10 hom., cov: 0)
• Consequence: HSPA5 NM_005347.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• Publications: 11 publications found

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]

HSPA5-DT (HGNC:55645): (HSPA5 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 1097 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA5	NM_005347.5	c.-384_-383insG		upstream_gene_variant		ENST00000324460.7	NP_005338.1
HSPA5-DT	NR_186826.1	n.-147_-146insC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA5	ENST00000324460.7	c.-384_-383insG		upstream_gene_variant		1	NM_005347.5	ENSP00000324173.6

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1098 AN: 151884 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00521

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00144

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00722 AC: 1097 AN: 152002 Hom.: 10 Cov.: 0 AF XY: 0.00665 AC XY: 494 AN XY: 74284

African (AFR) AF: 0.00246 AC: 102 AN: 41508

American (AMR) AF: 0.00354 AC: 54 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00521 AC: 55 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0122 AC: 829 AN: 67920

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00602 Hom.: 1397

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3216733; hg19: chr9-128003788;