rs397515338

Variant names:

• chr10-98490050-CTT-C
• rs397515338
• NM_021828.5:c.1465_1466delAA

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PVS1 PP3_Moderate PP5_Very_Strong BS1_Supporting

The NM_021828.5(HPSE2):​c.1465_1466delAA​(p.Asn489fs) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: HPSE2 NM_021828.5 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 5.80
• Publications: 6 publications found

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]

HPSE2 Gene-Disease associations (from GenCC):

• urofacial syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Ochoa syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-98490050-CTT-C is Pathogenic according to our data. Variant chr10-98490050-CTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 84.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 307 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021828.5. 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
	HPSE2	NM_021828.5	MANE Select	c.1465_1466delAA	p.Asn489fs	frameshift splice_region	Exon 10 of 12	NP_068600.4
	HPSE2	NM_001166246.1		c.1465_1466delAA	p.Asn489fs	frameshift splice_region	Exon 10 of 13	NP_001159718.1	Q8WWQ2-2
	HPSE2	NM_001166244.1		c.1291_1292delAA	p.Asn431fs	frameshift splice_region	Exon 9 of 11	NP_001159716.1	Q8WWQ2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPSE2	ENST00000370552.8	TSL:1 MANE Select	c.1465_1466delAA	p.Asn489fs	frameshift splice_region	Exon 10 of 12	ENSP00000359583.3	Q8WWQ2-1
	HPSE2	ENST00000370546.5	TSL:1	c.1465_1466delAA	p.Asn489fs	frameshift splice_region	Exon 10 of 13	ENSP00000359577.1	Q8WWQ2-2
	HPSE2	ENST00000370549.5	TSL:1	c.1291_1292delAA	p.Asn431fs	frameshift splice_region	Exon 9 of 11	ENSP00000359580.1	Q8WWQ2-3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152190 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251464 AF XY: 0.000140

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000563 AC: 626 AN: 1111968

Other (OTH) AF: 0.000348 AC: 21 AN: 60394

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74482

African (AFR) AF: 0.0000962 AC: 4 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000212

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Urofacial syndrome type 1 (7)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515338; hg19: chr10-100249807;