19-55274416-C-T

Variant names:

• chr19-55274416-C-T
• NM_012267.5:c.622G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012267.5(HSPBP1):​c.622G>A​(p.Ala208Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 6.62
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPBP1	NM_012267.5	MANE Select	c.622G>A	p.Ala208Thr	missense	Exon 4 of 8	NP_036399.3
	HSPBP1	NM_001297600.2		c.760G>A	p.Ala254Thr	missense	Exon 3 of 7	NP_001284529.1
	HSPBP1	NM_001130106.2		c.622G>A	p.Ala208Thr	missense	Exon 5 of 9	NP_001123578.1	Q9NZL4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPBP1	ENST00000433386.7	TSL:1 MANE Select	c.622G>A	p.Ala208Thr	missense	Exon 4 of 8	ENSP00000398244.1	Q9NZL4-1
	HSPBP1	ENST00000255631.9	TSL:1	c.622G>A	p.Ala208Thr	missense	Exon 5 of 9	ENSP00000255631.4	Q9NZL4-1
	HSPBP1	ENST00000587922.5	TSL:1	c.622G>A	p.Ala208Thr	missense	Exon 3 of 7	ENSP00000467574.1	Q9NZL4-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1184454 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 584644

African (AFR) AF: 0.00 AC: 0 AN: 25872

American (AMR) AF: 0.00 AC: 0 AN: 33864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16690

East Asian (EAS) AF: 0.00 AC: 0 AN: 15808

South Asian (SAS) AF: 0.00 AC: 0 AN: 80210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2906

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 946182

Other (OTH) AF: 0.00 AC: 0 AN: 43216

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.062	T
PhyloP100		6.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Vest4		0.89
MVP		0.84
MPC		0.97
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.57
Mutation Taster		=27/73	disease causing

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

Other links and lift over

hg19: chr19-55785784;