rs539689

Variant names:

• chr6-31829810-C-G
• rs539689
• NM_005346.6:c.1860C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005346.6(HSPA1B):​c.1860C>G​(p.Gly620Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 151,050 control chromosomes in the GnomAD database, including 21,143 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 0.52 (21143 hom., cov: 27)
  • Exomes 𝑓: 0.51 (195339 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1B NM_005346.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.52
• Publications: 24 publications found

Genes affected

HSPA1B (HGNC:5233): (heat shock protein family A (Hsp70) member 1B) This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

SNHG32 (HGNC:19078): (small nucleolar RNA host gene 32) Predicted to enable double-stranded RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1B	NM_005346.6	c.1860C>G	p.Gly620Gly	synonymous_variant	Exon 1 of 1	ENST00000375650.5	NP_005337.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1B	ENST00000375650.5	c.1860C>G	p.Gly620Gly	synonymous_variant	Exon 1 of 1	6	NM_005346.6	ENSP00000364801.3

Frequencies

GnomAD3 genomes AF: 0.523 AC: 78891 AN: 150932 Hom.: 21120 Cov.: 27

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.542

GnomAD2 exomes AF: 0.574 AC: 125453 AN: 218688 AF XY: 0.576

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.635

Gnomad EAS exome AF: 0.617

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.564

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.511 AC: 670450 AN: 1313160 Hom.: 195339 Cov.: 61 AF XY: 0.516 AC XY: 337559 AN XY: 653738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.440 AC: 13185 AN: 29956

American (AMR) AF: 0.705 AC: 27375 AN: 38850

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 14398 AN: 23180

East Asian (EAS) AF: 0.702 AC: 27270 AN: 38868

South Asian (SAS) AF: 0.652 AC: 51394 AN: 78820

European-Finnish (FIN) AF: 0.616 AC: 31356 AN: 50882

Middle Eastern (MID) AF: 0.595 AC: 3194 AN: 5372

European-Non Finnish (NFE) AF: 0.478 AC: 473882 AN: 992026

Other (OTH) AF: 0.514 AC: 28396 AN: 55206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.523 AC: 78955 AN: 151050 Hom.: 21143 Cov.: 27 AF XY: 0.533 AC XY: 39280 AN XY: 73716

African (AFR) AF: 0.454 AC: 18662 AN: 41146

American (AMR) AF: 0.635 AC: 9644 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2138 AN: 3462

East Asian (EAS) AF: 0.607 AC: 3090 AN: 5088

South Asian (SAS) AF: 0.651 AC: 3094 AN: 4752

European-Finnish (FIN) AF: 0.631 AC: 6580 AN: 10434

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.501 AC: 33927 AN: 67712

Other (OTH) AF: 0.546 AC: 1136 AN: 2082

Alfa AF: 0.521 Hom.: 3965

Bravo AF: 0.519

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.70
PhyloP100		-3.5
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: rs539689; hg19: chr6-31797587; COSMIC: COSV65128330; COSMIC: COSV65128330;