Variant chr4-83301004-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000311412.10(HPSE):c.1428T>G(p.Asp476Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,609,760 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

HPSE
ENST00000311412.10 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.607

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019448966).

BP6

Variant 4-83301004-A-C is Benign according to our data. Variant chr4-83301004-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3045667.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HPSE	NM_001098540.3 linkuse as main transcript	c.1428T>G	p.Asp476Glu	missense_variant	11/12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6 linkuse as main transcript	c.1428T>G	p.Asp476Glu	missense_variant	12/13		NP_006656.2
HPSE	NM_001199830.1 linkuse as main transcript	c.1254T>G	p.Asp418Glu	missense_variant	10/11		NP_001186759.1
HPSE	NM_001166498.3 linkuse as main transcript	c.1206T>G	p.Asp402Glu	missense_variant	10/11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10 linkuse as main transcript	c.1428T>G	p.Asp476Glu	missense_variant	11/12	1	NM_001098540.3	ENSP00000308107	P1	Q9Y251-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000789

AC:

197

AN:

249678

Hom.:

AF XY:

0.000755

AC XY:

102

AN XY:

135018

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000444

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.00139

AC:

2019

AN:

1457560

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

971

AN XY:

725382

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000405

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.000930

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152200

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.000744

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.000766

AC:

EpiCase

AF:

0.00137

EpiControl

AF:

0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HPSE-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2022

This variant is classified as likely 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

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.3

DANN

Benign

0.89

DEOGEN2

Benign

0.38

T;T;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.65

.;T;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.84

L;L;.;.

MutationTaster

Benign

0.81

D;D;D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.095

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.70

T;T;T;T

Polyphen

0.014

B;B;.;.

Vest4

0.13

MutPred

0.41

Gain of ubiquitination at K477 (P = 0.1278);Gain of ubiquitination at K477 (P = 0.1278);.;.;

MVP

0.17

MPC

0.089

ClinPred

0.060

GERP RS

-2.4

Varity_R

0.29

gMVP

0.49

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