4-83310857-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001098540.3(HPSE):c.707T>G(p.Phe236Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,613,758 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0057 ( 35 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.751

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009294599).

BP6

Variant 4-83310857-A-C is Benign according to our data. Variant chr4-83310857-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3042248.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HPSE	NM_001098540.3 linkuse as main transcript	c.707T>G	p.Phe236Cys	missense_variant	5/12	ENST00000311412.10
HPSE	NM_006665.6 linkuse as main transcript	c.707T>G	p.Phe236Cys	missense_variant	6/13
HPSE	NM_001199830.1 linkuse as main transcript	c.533T>G	p.Phe178Cys	missense_variant	4/11
HPSE	NM_001166498.3 linkuse as main transcript	c.707T>G	p.Phe236Cys	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPSE	ENST00000311412.10 linkuse as main transcript	c.707T>G	p.Phe236Cys	missense_variant	5/12	1	NM_001098540.3	P1	Q9Y251-1

Frequencies

GnomAD3 genomes

AF:

0.00429

AC:

653

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00706

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00430

AC:

1080

AN:

251190

Hom.:

AF XY:

0.00424

AC XY:

575

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00915

Gnomad NFE exome

AF:

0.00699

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00571

AC:

8349

AN:

1461430

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

4075

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.00652

Gnomad4 OTH exome

AF:

0.00556

GnomAD4 genome

AF:

0.00428

AC:

652

AN:

152328

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

310

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.00704

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00494

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00477

AC:

579

EpiCase

AF:

0.00519

EpiControl

AF:

0.00480

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HPSE-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2020

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

Benign

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.38

T;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.62

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.051

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.035

B;B;.;.

Vest4

0.31

MVP

0.31

MPC

0.13

ClinPred

0.028

GERP RS

2.7

Varity_R

0.29

gMVP

0.73

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