13-31147971-C-T

Variant summary

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

The NM_006644.4(HSPH1):​c.1366G>A​(p.Glu456Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,433,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HSPH1
NM_006644.4 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86
Variant links:
Genes affected
HSPH1 (HGNC:16969): (heat shock protein family H (Hsp110) member 1) This gene encodes a member of the heat shock protein 70 family of proteins. The encoded protein functions as a nucleotide exchange factor for the molecular chaperone heat shock cognate 71 kDa protein (Hsc70). In addition, this protein plays a distinct but related role as a holdase that inhibits the aggregation of misfolded proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Elevated expression of this protein has been observed in numerous human cancers. [provided by RefSeq, Mar 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HSPH1NM_006644.4 linkc.1366G>A p.Glu456Lys missense_variant Exon 10 of 18 ENST00000320027.10 NP_006635.2 Q92598-1A0A024RDS1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HSPH1ENST00000320027.10 linkc.1366G>A p.Glu456Lys missense_variant Exon 10 of 18 1 NM_006644.4 ENSP00000318687.5 Q92598-1
HSPH1ENST00000602786.5 linkn.*894G>A non_coding_transcript_exon_variant Exon 9 of 17 1 ENSP00000473512.1 R4GN69
HSPH1ENST00000602786.5 linkn.*894G>A 3_prime_UTR_variant Exon 9 of 17 1 ENSP00000473512.1 R4GN69

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000209
AC:
3
AN:
1433762
Hom.:
0
Cov.:
31
AF XY:
0.00000140
AC XY:
1
AN XY:
712928
show subpopulations
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:
0.00000272
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1366G>A (p.E456K) alteration is located in exon 10 (coding exon 10) of the HSPH1 gene. This alteration results from a G to A substitution at nucleotide position 1366, causing the glutamic acid (E) at amino acid position 456 to be replaced by a lysine (K). 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
AlphaMissense
Benign
0.22
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.075
T;T;.;.
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.44
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
.;L;.;L
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.5
.;D;.;N
REVEL
Benign
0.28
Sift
Uncertain
0.020
.;D;.;D
Sift4G
Uncertain
0.029
D;T;T;T
Polyphen
0.099, 0.081
.;B;.;B
Vest4
0.72
MutPred
0.65
.;Gain of methylation at E456 (P = 0.0071);.;Gain of methylation at E456 (P = 0.0071);
MVP
0.84
MPC
0.91
ClinPred
0.94
D
GERP RS
5.8
Varity_R
0.48
gMVP
0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1956328375; hg19: chr13-31722108; API