13-31148027-C-A

Variant names:

• chr13-31148027-C-A
• rs1478850712
• NM_006644.4:c.1310G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006644.4(HSPH1):​c.1310G>T​(p.Arg437Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41506127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPH1	NM_006644.4	c.1310G>T	p.Arg437Met	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.1310G>T	p.Arg437Met	missense_variant	Exon 10 of 18	1	NM_006644.4	ENSP00000318687.5
HSPH1	ENST00000602786.5	n.*838G>T		non_coding_transcript_exon_variant	Exon 9 of 17	1		ENSP00000473512.1
HSPH1	ENST00000602786.5	n.*838G>T		3_prime_UTR_variant	Exon 9 of 17	1		ENSP00000473512.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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 Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74262

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1310G>T (p.R437M) alteration is located in exon 10 (coding exon 10) of the HSPH1 gene. This alteration results from a G to T substitution at nucleotide position 1310, causing the arginine (R) at amino acid position 437 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.033	T;T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.3	.;L;.;L
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	.;N;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.88, 0.62	.;P;.;P
Vest4		0.40
MutPred		0.50		.;Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);
MVP		0.39
MPC		0.96
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.40

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: rs1478850712; hg19: chr13-31722164;