Genetic Variant HPSE:p.Leu480Pro (chr4-83300993-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001098540.3(HPSE):c.1439T>C(p.Leu480Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000618 in 1,455,774 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

Variant links:

Genes affected

HPSE (HGNC:5164): (heparanase) Heparan sulfate proteoglycans are major components of the basement membrane and extracellular matrix. The protein encoded by this gene is an enzyme that cleaves heparan sulfate proteoglycans to permit cell movement through remodeling of the extracellular matrix. In addition, this cleavage can release bioactive molecules from the extracellular matrix. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

HPSE links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3 link	c.1439T>C	p.Leu480Pro	missense_variant	Exon 11 of 12	ENST00000311412.10	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6 link	c.1439T>C	p.Leu480Pro	missense_variant	Exon 12 of 13		NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1 link	c.1265T>C	p.Leu422Pro	missense_variant	Exon 10 of 11		NP_001186759.1	Q9Y251-2
HPSE	NM_001166498.3 link	c.1217T>C	p.Leu406Pro	missense_variant	Exon 10 of 11		NP_001159970.1	Q9Y251-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10 link	c.1439T>C	p.Leu480Pro	missense_variant	Exon 11 of 12	1	NM_001098540.3	ENSP00000308107.5		Q9Y251-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247792

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134002

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1455774

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724430

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1439T>C (p.L480P) alteration is located in exon 12 (coding exon 11) of the HPSE gene. This alteration results from a T to C substitution at nucleotide position 1439, causing the leucine (L) at amino acid position 480 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;.;.

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.073

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.82

.;T;T;T

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

-0.0034

MutationAssessor

Pathogenic

3.1

M;M;.;.

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-5.5

D;D;D;D

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.79

MVP

0.58

MPC

0.58

ClinPred

0.95

GERP RS

4.6

Varity_R

0.87

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over