9-125238840-C-T

Variant names:

• chr9-125238840-C-T
• rs430397
• NM_005347.5:c.997-13G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005347.5(HSPA5):​c.997-13G>A variant causes a 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 NM_005347.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 35 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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HSPA5	NM_005347.5	c.997-13G>A		intron_variant	Intron 5 of 7	ENST00000324460.7	NP_005338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA5	ENST00000324460.7	c.997-13G>A		intron_variant	Intron 5 of 7	1	NM_005347.5	ENSP00000324173.6

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

GnomAD2 exomes AF: 0.0909 AC: 22788 AN: 250818 AF XY: 0.0908

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 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

African (AFR) AF: 0.194 AC: 6483 AN: 33362

American (AMR) AF: 0.0421 AC: 1880 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2859 AN: 26098

East Asian (EAS) AF: 0.138 AC: 5473 AN: 39684

South Asian (SAS) AF: 0.106 AC: 9129 AN: 86226

European-Finnish (FIN) AF: 0.0932 AC: 4975 AN: 53402

Middle Eastern (MID) AF: 0.116 AC: 668 AN: 5764

European-Non Finnish (NFE) AF: 0.0665 AC: 73847 AN: 1110686

Other (OTH) AF: 0.0872 AC: 5260 AN: 60318

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

African (AFR) AF: 0.191 AC: 7938 AN: 41468

American (AMR) AF: 0.0607 AC: 928 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3472

East Asian (EAS) AF: 0.154 AC: 798 AN: 5166

South Asian (SAS) AF: 0.119 AC: 572 AN: 4818

European-Finnish (FIN) AF: 0.0974 AC: 1031 AN: 10586

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0711 AC: 4832 AN: 67982

Other (OTH) AF: 0.0951 AC: 201 AN: 2114

Alfa AF: 0.0885 Hom.: 1455

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
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs430397; hg19: chr9-128001119; COSMIC: COSV107270503; COSMIC: COSV107270503;