Variant 4-83309479-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_001098540.3(HPSE):c.907C>T(p.Arg303Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000068 in 1,543,224 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 2 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity HPSE_HUMAN

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HPSE	NM_001098540.3 linkuse as main transcript	c.907C>T	p.Arg303Trp	missense_variant	7/12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6 linkuse as main transcript	c.907C>T	p.Arg303Trp	missense_variant	8/13		NP_006656.2
HPSE	NM_001199830.1 linkuse as main transcript	c.733C>T	p.Arg245Trp	missense_variant	6/11		NP_001186759.1
HPSE	NM_001166498.3 linkuse as main transcript	c.907C>T	p.Arg303Trp	missense_variant	8/11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10 linkuse as main transcript	c.907C>T	p.Arg303Trp	missense_variant	7/12	1	NM_001098540.3	ENSP00000308107	P1	Q9Y251-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000156

AC:

AN:

237234

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

128124

show subpopulations

Gnomad AFR exome

AF:

0.0000644

Gnomad AMR exome

AF:

0.000518

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000116

Gnomad SAS exome

AF:

0.000597

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000690

AC:

AN:

1391042

Hom.:

Cov.:

AF XY:

0.0000820

AC XY:

AN XY:

694832

show subpopulations

Gnomad4 AFR exome

AF:

0.0000641

Gnomad4 AMR exome

AF:

0.000460

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000772

Gnomad4 SAS exome

AF:

0.000705

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000852

Gnomad4 OTH exome

AF:

0.0000691

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000845

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000206

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

May 29, 2024

The c.907C>T (p.R303W) alteration is located in exon 8 (coding exon 7) of the HPSE gene. This alteration results from a C to T substitution at nucleotide position 907, causing the arginine (R) at amino acid position 303 to be replaced by a tryptophan (W). 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

Benign

0.21

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.61

D;D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Pathogenic

3.0

M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-6.7

D;D;D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.61

MutPred

0.77

Loss of ubiquitination at K307 (P = 0.0364);Loss of ubiquitination at K307 (P = 0.0364);Loss of ubiquitination at K307 (P = 0.0364);.;

MVP

0.48

MPC

0.49

ClinPred

0.43

GERP RS

4.0

Varity_R

0.91

gMVP

0.77

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