rs1203357768

Variant names:

• chr6-31817224-G-A
• rs1203357768
• NM_005345.6:c.1468G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_005345.6(HSPA1A):​c.1468G>A​(p.Ala490Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., cov: 12)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6	c.1468G>A	p.Ala490Thr	missense_variant	Exon 1 of 1	ENST00000375651.7	NP_005336.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1A	ENST00000375651.7	c.1468G>A	p.Ala490Thr	missense_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5
HSPA1A	ENST00000608703.2	c.973G>A	p.Ala325Thr	missense_variant	Exon 2 of 2	2		ENSP00000477378.1

Frequencies

GnomAD3 genomes AF: 0.00000934 AC: 1 AN: 107046 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0000379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000280 AC: 3 AN: 1071988 Hom.: 0 Cov.: 16 AF XY: 0.00000187 AC XY: 1 AN XY: 534470

African (AFR) AF: 0.0000796 AC: 2 AN: 25122

American (AMR) AF: 0.00 AC: 0 AN: 33624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20642

East Asian (EAS) AF: 0.00 AC: 0 AN: 34000

South Asian (SAS) AF: 0.00 AC: 0 AN: 68448

European-Finnish (FIN) AF: 0.0000228 AC: 1 AN: 43954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3346

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 796206

Other (OTH) AF: 0.00 AC: 0 AN: 46646

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000934 AC: 1 AN: 107046 Hom.: 0 Cov.: 12 AF XY: 0.0000204 AC XY: 1 AN XY: 49064

African (AFR) AF: 0.0000379 AC: 1 AN: 26410

American (AMR) AF: 0.00 AC: 0 AN: 9984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2732

East Asian (EAS) AF: 0.00 AC: 0 AN: 3960

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52342

Other (OTH) AF: 0.00 AC: 0 AN: 1294

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1468G>A (p.A490T) alteration is located in exon 1 (coding exon 1) of the HSPA1A gene. This alteration results from a G to A substitution at nucleotide position 1468, causing the alanine (A) at amino acid position 490 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.55	T
PhyloP100		7.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0080	D;D
Vest4		0.81
MutPred		0.80		Gain of glycosylation at A490 (P = 0.048);.;
MVP		0.48
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.27
gMVP		0.32
Mutation Taster		=71/29	polymorphism

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: rs1203357768; hg19: chr6-31785001;