chr13-31137439-G-A
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_006644.4(HSPH1):c.2456C>T(p.Pro819Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,372 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: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
HSPH1
NM_006644.4 missense
NM_006644.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 1.83
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.060691714).
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSPH1 | NM_006644.4 | c.2456C>T | p.Pro819Leu | missense_variant | 18/18 | ENST00000320027.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSPH1 | ENST00000320027.10 | c.2456C>T | p.Pro819Leu | missense_variant | 18/18 | 1 | NM_006644.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 151982Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250954Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135634
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461272Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726974
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GnomAD4 genome AF: 0.0000592 AC: 9AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74390
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The c.2456C>T (p.P819L) alteration is located in exon 18 (coding exon 18) of the HSPH1 gene. This alteration results from a C to T substitution at nucleotide position 2456, causing the proline (P) at amino acid position 819 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;D;.;D
REVEL
Benign
Sift
Uncertain
.;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
0.85, 0.12
.;P;.;.;B
Vest4
MutPred
0.22
.;Gain of catalytic residue at P819 (P = 0.1366);.;.;.;
MVP
MPC
0.44
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at