Variant 4-83295453-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001098540.3(HPSE):c.1523T>C(p.Leu508Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,752 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: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HPSE	NM_001098540.3 linkuse as main transcript	c.1523T>C	p.Leu508Ser	missense_variant	12/12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6 linkuse as main transcript	c.1523T>C	p.Leu508Ser	missense_variant	13/13		NP_006656.2
HPSE	NM_001199830.1 linkuse as main transcript	c.1349T>C	p.Leu450Ser	missense_variant	11/11		NP_001186759.1
HPSE	NM_001166498.3 linkuse as main transcript	c.1301T>C	p.Leu434Ser	missense_variant	11/11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10 linkuse as main transcript	c.1523T>C	p.Leu508Ser	missense_variant	12/12	1	NM_001098540.3	ENSP00000308107	P1	Q9Y251-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250904

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460752

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.1523T>C (p.L508S) alteration is located in exon 13 (coding exon 12) of the HPSE gene. This alteration results from a T to C substitution at nucleotide position 1523, causing the leucine (L) at amino acid position 508 to be replaced by a serine (S). 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

0.85

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.0

M;M;.;.

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.80

MutPred

0.65

Gain of disorder (P = 0.0101);Gain of disorder (P = 0.0101);.;.;

MVP

0.84

MPC

0.56

ClinPred

0.93

GERP RS

5.4

Varity_R

0.82

gMVP

0.92

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

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