Genetic Variant HSPBP1:p.Arg190Leu (chr19-55274469-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012267.5(HSPBP1):c.569G>T(p.Arg190Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSPBP1
NM_012267.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19442609).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPBP1	NM_012267.5	MANE Select	c.569G>T	p.Arg190Leu	missense	Exon 4 of 8	NP_036399.3
HSPBP1	NM_001297600.2		c.707G>T	p.Arg236Leu	missense	Exon 3 of 7	NP_001284529.1
HSPBP1	NM_001130106.2		c.569G>T	p.Arg190Leu	missense	Exon 5 of 9	NP_001123578.1	Q9NZL4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPBP1	ENST00000433386.7	TSL:1 MANE Select	c.569G>T	p.Arg190Leu	missense	Exon 4 of 8	ENSP00000398244.1	Q9NZL4-1
HSPBP1	ENST00000255631.9	TSL:1	c.569G>T	p.Arg190Leu	missense	Exon 5 of 9	ENSP00000255631.4	Q9NZL4-1
HSPBP1	ENST00000587922.5	TSL:1	c.569G>T	p.Arg190Leu	missense	Exon 3 of 7	ENSP00000467574.1	Q9NZL4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000495

AC:

AN:

202206

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000640

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1437272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713702

African (AFR)

AF:

0.00

AC:

AN:

33050

American (AMR)

AF:

0.00

AC:

AN:

42012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

38580

South Asian (SAS)

AF:

0.00

AC:

AN:

83354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103128

Other (OTH)

AF:

0.00

AC:

AN:

59414

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Benign

-0.077

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.81

M_CAP

Benign

0.015

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

PhyloP100

2.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.2

REVEL

Benign

0.072

Sift

Benign

0.16

Sift4G

Benign

0.16

Vest4

0.48

MVP

0.42

MPC

0.37

ClinPred

0.29

GERP RS

5.6

Varity_R

0.30

gMVP

0.38

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over