Genetic Variant HSPBP1:p.Arg324His (chr19-55265312-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012267.5(HSPBP1):c.971G>A(p.Arg324His) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,612,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

HSPBP1
NM_012267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

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]

HSPBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPBP1	NM_012267.5 link	c.971G>A	p.Arg324His	missense_variant	Exon 7 of 8	ENST00000433386.7	NP_036399.3	Q9NZL4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSPBP1	ENST00000433386.7 link	c.971G>A	p.Arg324His	missense_variant	Exon 7 of 8	1	NM_012267.5	ENSP00000398244.1	Q9NZL4-1
HSPBP1	ENST00000255631.9 link	c.971G>A	p.Arg324His	missense_variant	Exon 8 of 9	1		ENSP00000255631.4	Q9NZL4-1
HSPBP1	ENST00000587922.5 link	c.971G>A	p.Arg324His	missense_variant	Exon 6 of 7	1		ENSP00000467574.1	Q9NZL4-1
HSPBP1	ENST00000585927.1 link	c.501-8G>A		splice_region_variant, intron_variant	Intron 3 of 4	5		ENSP00000466569.1	K7EMM7

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249884

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461188

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74022

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.971G>A (p.R324H) alteration is located in exon 7 (coding exon 6) of the HSPBP1 gene. This alteration results from a G to A substitution at nucleotide position 971, causing the arginine (R) at amino acid position 324 to be replaced by a histidine (H). 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

Uncertain

0.50

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

.;.;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.80

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.075

T;T;.

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.59

MVP

0.52

MPC

0.40

ClinPred

0.98

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.51

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over