rs397515338

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting

The ENST00000370552.8(HPSE2):​c.1465_1466del​(p.Asn489ProfsTer126) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000419 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β˜…β˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

HPSE2
ENST00000370552.8 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.80
Variant links:
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 17 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-98490050-CTT-C is Pathogenic according to our data. Variant chr10-98490050-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 84.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98490050-CTT-C is described in Lovd as [Pathogenic]. Variant chr10-98490050-CTT-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000445 (650/1461836) while in subpopulation NFE AF= 0.000563 (626/1111968). AF 95% confidence interval is 0.000526. There are 0 homozygotes in gnomad4_exome. There are 307 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HPSE2NM_021828.5 linkuse as main transcriptc.1465_1466del p.Asn489ProfsTer126 frameshift_variant, splice_region_variant 10/12 ENST00000370552.8 NP_068600.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HPSE2ENST00000370552.8 linkuse as main transcriptc.1465_1466del p.Asn489ProfsTer126 frameshift_variant, splice_region_variant 10/121 NM_021828.5 ENSP00000359583 P1Q8WWQ2-1

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
39
AN:
251464
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000308
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000445
AC:
650
AN:
1461836
Hom.:
0
AF XY:
0.000422
AC XY:
307
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000563
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.000212
EpiCase
AF:
0.000273
EpiControl
AF:
0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Urofacial syndrome type 1 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 11, 2019- -
not provided, no classification providedliterature onlyGeneReviews-- -
Likely pathogenic, criteria provided, single submitterclinical testingEurofins-BiomnisDec 13, 2022- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 17, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 22, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 11, 2010- -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 18, 2023Frameshift variant predicted to result in the deletion of the last 104 amino acids, replaced with 125 incorrect amino acids; This variant is associated with the following publications: (PMID: 20560209, 11446407, 31589614, 35812751, 20560210) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 21, 2023Algorithms 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. ClinVar contains an entry for this variant (Variation ID: 84). This premature translational stop signal has been observed in individuals with urofacial syndrome (PMID: 20560209, 20560210). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397515338, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Asn489Profs*126) in the HPSE2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the HPSE2 protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.99
Position offset: 3
DS_DL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515338; hg19: chr10-100249807; API