rs267606866
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_021828.5(HPSE2):c.1516C>T(p.Arg506Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000124 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
HPSE2
NM_021828.5 stop_gained
NM_021828.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 6.27
Genes affected
HPSE2 (HGNC:18374): (heparanase 2 (inactive)) This gene encodes a heparanase enzyme. The encoded protein is a endoglycosidase that degrades heparin sulfate proteoglycans located on the extracellular matrix and cell surface. This protein may be involved in biological processes involving remodeling of the extracellular matrix including angiogenesis and tumor progression. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.148 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-98482733-G-A is Pathogenic according to our data. Variant chr10-98482733-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 83.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98482733-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HPSE2 | NM_021828.5 | c.1516C>T | p.Arg506Ter | stop_gained | 11/12 | ENST00000370552.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPSE2 | ENST00000370552.8 | c.1516C>T | p.Arg506Ter | stop_gained | 11/12 | 1 | NM_021828.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
2
AN:
152144
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251422Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135874
GnomAD3 exomes
AF:
AC:
4
AN:
251422
Hom.:
AF XY:
AC XY:
3
AN XY:
135874
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727224
GnomAD4 exome
AF:
AC:
18
AN:
1461830
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
727224
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74322
GnomAD4 genome
?
AF:
AC:
2
AN:
152144
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74322
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
?
AF:
AC:
3
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Urofacial syndrome type 1 Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Dec 13, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 11, 2010 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2023 | ClinVar contains an entry for this variant (Variation ID: 83). This premature translational stop signal has been observed in individual(s) with urofacial syndrome (PMID: 20560209). This variant is present in population databases (rs267606866, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg506*) in the HPSE2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPSE2 are known to be pathogenic (PMID: 20560210, 25510506). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
0.46, 0.42, 0.46
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 49
Find out detailed SpliceAI scores and Pangolin per-transcript scores at