13-31137382-G-C

Variant names:

• chr13-31137382-G-C
• rs1955919196
• NM_006644.4:c.2513C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006644.4(HSPH1):​c.2513C>G​(p.Pro838Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPH1 NM_006644.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060450047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPH1	NM_006644.4	c.2513C>G	p.Pro838Arg	missense_variant	Exon 18 of 18	ENST00000320027.10	NP_006635.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPH1	ENST00000320027.10	c.2513C>G	p.Pro838Arg	missense_variant	Exon 18 of 18	1	NM_006644.4	ENSP00000318687.5
HSPH1	ENST00000602786.5	n.*2041C>G		non_coding_transcript_exon_variant	Exon 17 of 17	1		ENSP00000473512.1
HSPH1	ENST00000602786.5	n.*2041C>G		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000473512.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2513C>G (p.P838R) alteration is located in exon 18 (coding exon 18) of the HSPH1 gene. This alteration results from a C to G substitution at nucleotide position 2513, causing the proline (P) at amino acid position 838 to be replaced by an arginine (R). 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	0.092
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.026	T;T;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.85	D;T;D;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.060	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	.;L;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.84	.;N;N;.;N
REVEL	Benign	0.057
Sift	Benign	0.14	.;T;T;.;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.0020, 0.0070	.;B;.;.;B
Vest4		0.13
MutPred		0.29		.;Gain of solvent accessibility (P = 0.0584);.;.;.;
MVP		0.34
MPC		0.44
ClinPred		0.073	T
GERP RS		3.0
Varity_R		0.041
gMVP		0.30

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: rs1955919196; hg19: chr13-31711519;