chr19-55274512-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012267.5(HSPBP1):​c.526G>A​(p.Val176Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000063 in 1,603,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

HSPBP1
NM_012267.5 missense

Scores

1
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.78
Variant links:
Genes affected
HSPBP1 (HGNC:24989): (HSPA (Hsp70) binding protein 1) Enables ubiquitin protein ligase binding activity. Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process and positive regulation of protein ubiquitination. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19603902).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HSPBP1NM_012267.5 linkc.526G>A p.Val176Met missense_variant Exon 4 of 8 ENST00000433386.7 NP_036399.3 Q9NZL4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HSPBP1ENST00000433386.7 linkc.526G>A p.Val176Met missense_variant Exon 4 of 8 1 NM_012267.5 ENSP00000398244.1 Q9NZL4-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152208
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000266
AC:
6
AN:
225218
Hom.:
0
AF XY:
0.0000323
AC XY:
4
AN XY:
123978
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000605
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000641
AC:
93
AN:
1451084
Hom.:
1
Cov.:
36
AF XY:
0.0000651
AC XY:
47
AN XY:
721626
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
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:
0.0000802
Gnomad4 OTH exome
AF:
0.0000501
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152208
Hom.:
0
Cov.:
31
AF XY:
0.0000672
AC XY:
5
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000176
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 06, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.526G>A (p.V176M) alteration is located in exon 4 (coding exon 3) of the HSPBP1 gene. This alteration results from a G to A substitution at nucleotide position 526, causing the valine (V) at amino acid position 176 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
0.32
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0062
.;.;.;T;T;T
Eigen
Benign
-0.0054
Eigen_PC
Benign
0.069
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.76
.;.;T;T;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.20
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
0.55
N;N;.;.;.;.
REVEL
Benign
0.11
Sift
Benign
0.18
T;T;.;.;.;.
Sift4G
Benign
0.24
T;T;T;D;.;T
Vest4
0.33
MVP
0.35
MPC
0.96
ClinPred
0.19
T
GERP RS
3.5
Varity_R
0.21
gMVP
0.14

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780645577; hg19: chr19-55785880; API