NM_005345.6:c.1780C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 0 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1A	NM_005345.6	MANE Select	c.1780C>T	p.His594Tyr	missense	Exon 1 of 1	NP_005336.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1A	ENST00000375651.7	TSL:6 MANE Select	c.1780C>T	p.His594Tyr	missense	Exon 1 of 1	ENSP00000364802.5	P0DMV8-1
	HSPA1A	ENST00000608703.2	TSL:2	c.1285C>T	p.His429Tyr	missense	Exon 2 of 2	ENSP00000477378.1	V9GZ37

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
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
MetaSVM	Benign	-1.2	T
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	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
Mutation Taster		=94/6	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

hg19: chr6-31785313;