rs397515452

Positions:

• chr10-98459725-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_021828.5(HPSE2):​c.1628A>T​(p.Asn543Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,364 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HPSE2 NM_021828.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 10-98459725-T-A is Pathogenic according to our data. Variant chr10-98459725-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 60719.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPSE2	NM_021828.5	c.1628A>T	p.Asn543Ile	missense_variant	12/12	ENST00000370552.8	NP_068600.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE2	ENST00000370552.8	c.1628A>T	p.Asn543Ile	missense_variant	12/12	1	NM_021828.5	ENSP00000359583	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461364 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 726934

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Urofacial syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.9	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.3	.;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0, 0.97	.;D;D;D
Vest4		0.99, 0.94, 0.92
MutPred		0.73		.;Loss of disorder (P = 0.0294);.;.;
MVP		0.85
MPC		0.76
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.87

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: rs397515452; hg19: chr10-100219482;