rs1008438

Variant names:

• chr6-31815431-A-C
• rs1008438
• NM_005345.6:c.-326A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-31815431-A-C
• chr6-31815431-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005345.6(HSPA1A):​c.-326A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 596,576 control chromosomes in the GnomAD database, including 59,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.51 (21347 hom., cov: 31)
  • Exomes 𝑓: 0.40 (37936 hom.)
• Consequence: HSPA1A NM_005345.6 upstream_gene
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.162
• Publications: 54 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]

HSPA1L (HGNC:5234): (heat shock protein family A (Hsp70) member 1 like) This gene encodes a 70kDa heat shock protein. In conjunction 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. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6	c.-326A>C		upstream_gene_variant		ENST00000375651.7	NP_005336.3
HSPA1L	NM_005527.4	c.-556T>G		upstream_gene_variant		ENST00000375654.5	NP_005518.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1A	ENST00000375651.7	c.-326A>C		upstream_gene_variant		6	NM_005345.6	ENSP00000364802.5
HSPA1L	ENST00000375654.5	c.-556T>G		upstream_gene_variant		1	NM_005527.4	ENSP00000364805.4
HSPA1A	ENST00000608703.2	c.-326A>C		upstream_gene_variant		2		ENSP00000477378.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76984 AN: 151764 Hom.: 21320 Cov.: 31

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.402 AC: 178819 AN: 444694 Hom.: 37936 Cov.: 4 AF XY: 0.401 AC XY: 94639 AN XY: 235736

African (AFR) AF: 0.740 AC: 8931 AN: 12076

American (AMR) AF: 0.474 AC: 8504 AN: 17936

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 4994 AN: 13104

East Asian (EAS) AF: 0.411 AC: 11979 AN: 29172

South Asian (SAS) AF: 0.459 AC: 20883 AN: 45496

European-Finnish (FIN) AF: 0.475 AC: 12823 AN: 27000

Middle Eastern (MID) AF: 0.391 AC: 749 AN: 1918

European-Non Finnish (NFE) AF: 0.363 AC: 99041 AN: 272844

Other (OTH) AF: 0.434 AC: 10915 AN: 25148

GnomAD4 genome AF: 0.507 AC: 77056 AN: 151882 Hom.: 21347 Cov.: 31 AF XY: 0.509 AC XY: 37810 AN XY: 74226

African (AFR) AF: 0.743 AC: 30785 AN: 41440

American (AMR) AF: 0.498 AC: 7601 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1310 AN: 3466

East Asian (EAS) AF: 0.414 AC: 2132 AN: 5144

South Asian (SAS) AF: 0.484 AC: 2332 AN: 4814

European-Finnish (FIN) AF: 0.493 AC: 5194 AN: 10530

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26230 AN: 67906

Other (OTH) AF: 0.517 AC: 1089 AN: 2106

Alfa AF: 0.255 Hom.: 512

Bravo AF: 0.518

Asia WGS AF: 0.550 AC: 1910 AN: 3478

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		-0.16
PromoterAI		0.0024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1008438; hg19: chr6-31783208;