chr6-31817536-C-T

Variant names:

• chr6-31817536-C-T
• NM_005345.6:c.1780C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005345.6(HSPA1A):​c.1780C>T​(p.His594Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25505206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6	c.1780C>T	p.His594Tyr	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.1780C>T	p.His594Tyr	missense_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5
HSPA1A	ENST00000608703.1	c.1285C>T	p.His429Tyr	missense_variant	Exon 2 of 2	2		ENSP00000477378.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460480 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1780C>T (p.H594Y) alteration is located in exon 1 (coding exon 1) of the HSPA1A gene. This alteration results from a C to T substitution at nucleotide position 1780, causing the histidine (H) at amino acid position 594 to be replaced by a tyrosine (Y). 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	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.21	T;T
Vest4		0.44
MutPred		0.46		Loss of methylation at K597 (P = 0.0528);.;
MVP		0.27
ClinPred		0.98	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31785313;