Genetic Variant HPSE:p.Gly370Asp (chr4-83306300-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001098540.3(HPSE):c.1109G>A(p.Gly370Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0014 in 1,610,798 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.05

Publications

7 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 4-83306300-C-T is Benign according to our data. Variant chr4-83306300-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 737153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPSE	NM_001098540.3	MANE Select	c.1109G>A	p.Gly370Asp	missense	Exon 9 of 12	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6		c.1109G>A	p.Gly370Asp	missense	Exon 10 of 13	NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1		c.935G>A	p.Gly312Asp	missense	Exon 8 of 11	NP_001186759.1	Q9Y251-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPSE	ENST00000311412.10	TSL:1 MANE Select	c.1109G>A	p.Gly370Asp	missense	Exon 9 of 12	ENSP00000308107.5	Q9Y251-1
HPSE	ENST00000405413.6	TSL:1	c.1109G>A	p.Gly370Asp	missense	Exon 10 of 13	ENSP00000384262.2	Q9Y251-1
HPSE	ENST00000513463.1	TSL:1	c.935G>A	p.Gly312Asp	missense	Exon 8 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000883

AC:

222

AN:

251306

AF XY:

0.000884

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00142

AC:

2072

AN:

1458470

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1012

AN XY:

725892

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33414

American (AMR)

AF:

0.000470

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000371

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00173

AC:

1917

AN:

1108928

Other (OTH)

AF:

0.00124

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00118

AC:

179

AN:

152328

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41578

American (AMR)

AF:

0.000915

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.00126

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000997

AC:

121

EpiCase

AF:

0.00180

EpiControl

AF:

0.00125

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

0.071

MutationAssessor

Pathogenic

3.3

PhyloP100

7.1

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.83

MPC

0.54

ClinPred

0.11

GERP RS

5.1

Varity_R

0.99

gMVP

0.96

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over