rs562047

Positions:

• chr6-31816086-G-C

Variant summary

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

The NM_005345.6(HSPA1A):​c.330G>C​(p.Glu110Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (831 hom., cov: 6)
  • Exomes 𝑓: 0.12 (5806 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 3.54

Genes affected

HSPA1A (HGNC:5232): (heat shock protein family A (Hsp70) member 1A) 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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033769608).
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1A	NM_005345.6	c.330G>C	p.Glu110Asp	missense_variant	1/1	ENST00000375651.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1A	ENST00000375651.7	c.330G>C	p.Glu110Asp	missense_variant	1/1		NM_005345.6	P1
HSPA1A	ENST00000608703.1	c.76-241G>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5461 AN: 35902 Hom.: 828 Cov.: 6 FAILED QC

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.0309

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.0856

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.158 AC: 10593 AN: 67108 Hom.: 1140 AF XY: 0.153 AC XY: 5272 AN XY: 34434

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.0756

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.124 AC: 71861 AN: 581384 Hom.: 5806 Cov.: 7 AF XY: 0.123 AC XY: 37004 AN XY: 301390

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.0865

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0762

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.152 AC: 5467 AN: 35910 Hom.: 831 Cov.: 6 AF XY: 0.155 AC XY: 2279 AN XY: 14728

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.0746

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0522

Gnomad4 NFE AF: 0.0856

Gnomad4 OTH AF: 0.204

Alfa AF: 0.162 Hom.: 407

ExAC AF: 0.0481 AC: 1492

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic obstructive pulmonary disease Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Aug 04, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.0041
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0000035	P;P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.11
Sift	Benign	0.042	D
Sift4G	Uncertain	0.029	D
Vest4		0.059
MutPred		0.24		Loss of phosphorylation at Y107 (P = 0.0735);
ClinPred		0.013	T
GERP RS		3.5
Varity_R		0.56
gMVP		0.18

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: rs562047; hg19: chr6-31783863; COSMIC: COSV65148669; COSMIC: COSV65148669;