9-125235313-G-A

Variant names:

• chr9-125235313-G-A
• rs1140763
• NM_005347.5:c.*1279C>T

Variant summary

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

The NM_005347.5(HSPA5):​c.*1279C>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 0.527 in 150,324 control chromosomes in the GnomAD database, including 21,085 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 0.53 (21064 hom., cov: 26)
  • Exomes 𝑓: 0.56 (21 hom.)
• Consequence: HSPA5 NM_005347.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 10 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005347.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA5	NM_005347.5	MANE Select	c.*1279C>T		3_prime_UTR	Exon 8 of 8	NP_005338.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA5	ENST00000324460.7	TSL:1 MANE Select	c.*1279C>T		3_prime_UTR	Exon 8 of 8	ENSP00000324173.6
	HSPA5	ENST00000679355.1		n.3599C>T		non_coding_transcript_exon	Exon 7 of 7
	HSPA5	ENST00000679475.1		n.3828C>T		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79093 AN: 150088 Hom.: 21052 Cov.: 26

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.587

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.544

GnomAD4 exome AF: 0.559 AC: 66 AN: 118 Hom.: 21 Cov.: 0 AF XY: 0.532 AC XY: 50 AN XY: 94

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 3 AN: 6

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.561 AC: 55 AN: 98

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.527 AC: 79142 AN: 150206 Hom.: 21064 Cov.: 26 AF XY: 0.531 AC XY: 38909 AN XY: 73268

African (AFR) AF: 0.476 AC: 19366 AN: 40708

American (AMR) AF: 0.554 AC: 8307 AN: 14988

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1615 AN: 3464

East Asian (EAS) AF: 0.464 AC: 2340 AN: 5046

South Asian (SAS) AF: 0.525 AC: 2478 AN: 4720

European-Finnish (FIN) AF: 0.658 AC: 6821 AN: 10364

Middle Eastern (MID) AF: 0.586 AC: 170 AN: 290

European-Non Finnish (NFE) AF: 0.539 AC: 36442 AN: 67658

Other (OTH) AF: 0.544 AC: 1121 AN: 2062

Alfa AF: 0.523 Hom.: 2564

Bravo AF: 0.515

Asia WGS AF: 0.490 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.7
DANN	Benign	0.78
PhyloP100		0.25
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: rs1140763; hg19: chr9-127997592;