19-55265956-G-C

Position:

• chr19-55265956-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012267.5(HSPBP1):​c.823C>G​(p.Gln275Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,453,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HSPBP1 NM_012267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13473096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPBP1	NM_012267.5	c.823C>G	p.Gln275Glu	missense_variant	6/8	ENST00000433386.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPBP1	ENST00000433386.7	c.823C>G	p.Gln275Glu	missense_variant	6/8	1	NM_012267.5	P1
HSPBP1	ENST00000255631.9	c.823C>G	p.Gln275Glu	missense_variant	7/9	1		P1
HSPBP1	ENST00000587922.5	c.823C>G	p.Gln275Glu	missense_variant	5/7	1		P1
HSPBP1	ENST00000585927.1	c.501-652C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1453894 Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4 AN XY: 722470

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: 0.00000721

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.823C>G (p.Q275E) alteration is located in exon 6 (coding exon 5) of the HSPBP1 gene. This alteration results from a C to G substitution at nucleotide position 823, causing the glutamine (Q) at amino acid position 275 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Benign	0.69
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.54	N;N;.
REVEL	Benign	0.14
Sift	Benign	0.84	T;T;.
Sift4G	Benign	0.75	T;T;T
Vest4		0.27
MVP		0.16
MPC		0.32
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.31
gMVP		0.10

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: rs758612420; hg19: chr19-55777324;