13-31147971-C-T

Variant names:

• chr13-31147971-C-T
• rs1956328375
• NM_006644.4:c.1366G>A

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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]

ACMG classification

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
HSPH1	NM_006644.4	c.1366G>A	p.Glu456Lys	missense_variant	Exon 10 of 18	ENST00000320027.10	NP_006635.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPH1	ENST00000320027.10	c.1366G>A	p.Glu456Lys	missense_variant	Exon 10 of 18	1	NM_006644.4	ENSP00000318687.5
HSPH1	ENST00000602786.5	n.*894G>A		non_coding_transcript_exon_variant	Exon 9 of 17	1		ENSP00000473512.1
HSPH1	ENST00000602786.5	n.*894G>A		3_prime_UTR_variant	Exon 9 of 17	1		ENSP00000473512.1

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

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

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

Other links and lift over

dbSNP: rs1956328375; hg19: chr13-31722108;