19-55266227-C-A

Variant names:

• chr19-55266227-C-A
• rs1180126843
• NM_012267.5:c.700G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012267.5(HSPBP1):​c.700G>T​(p.Val234Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPBP1 NM_012267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31829643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPBP1	NM_012267.5	c.700G>T	p.Val234Leu	missense_variant	Exon 5 of 8	ENST00000433386.7	NP_036399.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPBP1	ENST00000433386.7	c.700G>T	p.Val234Leu	missense_variant	Exon 5 of 8	1	NM_012267.5	ENSP00000398244.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000494 AC: 1 AN: 202238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 109038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000653

Gnomad SAS exome AF: 0.00

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: 0 AN: 1432500 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 710068

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.700G>T (p.V234L) alteration is located in exon 5 (coding exon 4) of the HSPBP1 gene. This alteration results from a G to T substitution at nucleotide position 700, causing the valine (V) at amino acid position 234 to be replaced by a leucine (L). 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	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.78	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N;N;.
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;D;.
Sift4G	Benign	0.13	T;T;T
Vest4		0.52
MVP		0.39
MPC		0.31
ClinPred		0.55	D
GERP RS		4.8
Varity_R		0.50
gMVP		0.49

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

Other links and lift over

dbSNP: rs1180126843; hg19: chr19-55777595;