Genetic Variant HPSE:p.Asn459Asn (chr4-83301055-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001098540.3(HPSE):c.1377T>C(p.Asn459Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,607,680 control chromosomes in the GnomAD database, including 2,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.073 ( 1380 hom., cov: 31)

Exomes 𝑓: 0.0078 ( 1175 hom. )

Consequence

HPSE
NM_001098540.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.668

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 4-83301055-A-G is Benign according to our data. Variant chr4-83301055-A-G is described in ClinVar as [Benign]. Clinvar id is 3037827.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.668 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3 link	c.1377T>C	p.Asn459Asn	synonymous_variant	Exon 11 of 12	ENST00000311412.10	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6 link	c.1377T>C	p.Asn459Asn	synonymous_variant	Exon 12 of 13		NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1 link	c.1203T>C	p.Asn401Asn	synonymous_variant	Exon 10 of 11		NP_001186759.1	Q9Y251-2
HPSE	NM_001166498.3 link	c.1155T>C	p.Asn385Asn	synonymous_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.1377T>C	p.Asn459Asn	synonymous_variant	Exon 11 of 12	1	NM_001098540.3	ENSP00000308107.5		Q9Y251-1

Frequencies

GnomAD3 genomes

AF:

0.0727

AC:

11065

AN:

152108

Hom.:

1371

Cov.:

show subpopulations

Gnomad AFR

AF:

0.251

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0270

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.0521

GnomAD3 exomes

AF:

0.0193

AC:

4785

AN:

248048

Hom.:

563

AF XY:

0.0143

AC XY:

1915

AN XY:

134166

show subpopulations

Gnomad AFR exome

AF:

0.257

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.000900

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00849

GnomAD4 exome

AF:

0.00777

AC:

11315

AN:

1455456

Hom.:

1175

Cov.:

AF XY:

0.00681

AC XY:

4930

AN XY:

724392

show subpopulations

Gnomad4 AFR exome

AF:

0.253

Gnomad4 AMR exome

AF:

0.0151

Gnomad4 ASJ exome

AF:

0.00288

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000865

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.000808

Gnomad4 OTH exome

AF:

0.0187

GnomAD4 genome

AF:

0.0729

AC:

11103

AN:

152224

Hom.:

1380

Cov.:

AF XY:

0.0711

AC XY:

5291

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.252

Gnomad4 AMR

AF:

0.0269

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.0516

Alfa

AF:

0.0346

Hom.:

354

Bravo

AF:

0.0836

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HPSE-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.3

DANN

Benign

0.38

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