6-31816086-G-C

Variant names:

• chr6-31816086-G-C
• rs562047
• NM_005345.6:c.330G>C

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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
• Publications: 18 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005345.6. 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
	HSPA1A	NM_005345.6	MANE Select	c.330G>C	p.Glu110Asp	missense	Exon 1 of 1	NP_005336.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1A	ENST00000375651.7	TSL:6 MANE Select	c.330G>C	p.Glu110Asp	missense	Exon 1 of 1	ENSP00000364802.5
	HSPA1A	ENST00000608703.2	TSL:2	c.76-241G>C		intron	N/A	ENSP00000477378.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 5461 AN: 35902 Hom.: 828 Cov.: 6

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

GnomAD2 exomes AF: 0.158 AC: 10593 AN: 67108 AF XY: 0.153

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 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

African (AFR) AF: 0.435 AC: 6638 AN: 15256

American (AMR) AF: 0.160 AC: 3883 AN: 24248

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 3645 AN: 15330

East Asian (EAS) AF: 0.0865 AC: 2756 AN: 31868

South Asian (SAS) AF: 0.138 AC: 7070 AN: 51088

European-Finnish (FIN) AF: 0.0762 AC: 2278 AN: 29902

Middle Eastern (MID) AF: 0.205 AC: 464 AN: 2262

European-Non Finnish (NFE) AF: 0.107 AC: 40725 AN: 380994

Other (OTH) AF: 0.145 AC: 4402 AN: 30436

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

African (AFR) AF: 0.378 AC: 2581 AN: 6822

American (AMR) AF: 0.163 AC: 545 AN: 3344

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 206 AN: 1100

East Asian (EAS) AF: 0.0746 AC: 146 AN: 1956

South Asian (SAS) AF: 0.117 AC: 150 AN: 1284

European-Finnish (FIN) AF: 0.0522 AC: 106 AN: 2032

Middle Eastern (MID) AF: 0.218 AC: 38 AN: 174

European-Non Finnish (NFE) AF: 0.0856 AC: 1583 AN: 18484

Other (OTH) AF: 0.204 AC: 106 AN: 520

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

Aug 04, 2019

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
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
PhyloP100		3.5
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
Mutation Taster		=92/8	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: rs562047; hg19: chr6-31783863; COSMIC: COSV65148669; COSMIC: COSV65148669;