13-31137500-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006644.4(HSPH1):​c.2395G>A​(p.Val799Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

HSPH1
NM_006644.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0720
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011989266).
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HSPH1NM_006644.4 linkuse as main transcriptc.2395G>A p.Val799Ile missense_variant 18/18 ENST00000320027.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HSPH1ENST00000320027.10 linkuse as main transcriptc.2395G>A p.Val799Ile missense_variant 18/181 NM_006644.4 P1Q92598-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000678
AC:
17
AN:
250806
Hom.:
0
AF XY:
0.0000664
AC XY:
9
AN XY:
135572
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000595
AC:
87
AN:
1461168
Hom.:
0
Cov.:
31
AF XY:
0.0000743
AC XY:
54
AN XY:
726890
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000720
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

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 submitterclinical testingAmbry GeneticsJan 23, 2023The c.2395G>A (p.V799I) alteration is located in exon 18 (coding exon 18) of the HSPH1 gene. This alteration results from a G to A substitution at nucleotide position 2395, causing the valine (V) at amino acid position 799 to be replaced by an isoleucine (I). 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
0.066
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
13
DANN
Benign
0.31
DEOGEN2
Benign
0.0031
T;T;.;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.069
N
LIST_S2
Benign
0.81
T;T;T;T;T
M_CAP
Benign
0.0076
T
MetaRNN
Benign
0.012
T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
-0.69
.;N;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
0.49
.;N;N;.;N
REVEL
Benign
0.020
Sift
Benign
1.0
.;T;T;.;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0020, 0.0080
.;B;.;.;B
Vest4
0.092
MVP
0.18
MPC
0.33
ClinPred
0.0082
T
GERP RS
2.1
Varity_R
0.010
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs140348808; hg19: chr13-31711637; COSMIC: COSV60710601; COSMIC: COSV60710601; API