Genetic Variant HPSE:c.674-61A>G (chr4-83310951-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001098540.3(HPSE):c.674-61A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,324,120 control chromosomes in the GnomAD database, including 407,992 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.80 ( 48316 hom., cov: 33)

Exomes 𝑓: 0.78 ( 359676 hom. )

Consequence

HPSE
NM_001098540.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.29

Publications

13 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HPSE	NM_001098540.3 link	c.674-61A>G	intron_variant	Intron 4 of 11	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6 link	c.674-61A>G	intron_variant	Intron 5 of 12		NP_006656.2
HPSE	NM_001199830.1 link	c.500-61A>G	intron_variant	Intron 3 of 10		NP_001186759.1
HPSE	NM_001166498.3 link	c.674-61A>G	intron_variant	Intron 5 of 10		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10 link	c.674-61A>G		intron_variant	Intron 4 of 11	1	NM_001098540.3	ENSP00000308107.5

Frequencies

GnomAD3 genomes

AF:

0.796

AC:

121004

AN:

152082

Hom.:

48283

Cov.:

show subpopulations

Gnomad AFR

AF:

0.852

Gnomad AMI

AF:

0.611

Gnomad AMR

AF:

0.743

Gnomad ASJ

AF:

0.794

Gnomad EAS

AF:

0.871

Gnomad SAS

AF:

0.807

Gnomad FIN

AF:

0.760

Gnomad MID

AF:

0.769

Gnomad NFE

AF:

0.775

Gnomad OTH

AF:

0.783

GnomAD4 exome

AF:

0.783

AC:

917656

AN:

1171920

Hom.:

359676

AF XY:

0.783

AC XY:

462859

AN XY:

590826

show subpopulations

African (AFR)

AF:

0.856

AC:

22661

AN:

26474

American (AMR)

AF:

0.713

AC:

23946

AN:

33576

Ashkenazi Jewish (ASJ)

AF:

0.798

AC:

17371

AN:

21770

East Asian (EAS)

AF:

0.846

AC:

32187

AN:

38058

South Asian (SAS)

AF:

0.792

AC:

57550

AN:

72682

European-Finnish (FIN)

AF:

0.765

AC:

38736

AN:

50622

Middle Eastern (MID)

AF:

0.781

AC:

3900

AN:

4992

European-Non Finnish (NFE)

AF:

0.780

AC:

681588

AN:

873430

Other (OTH)

AF:

0.789

AC:

39717

AN:

50316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

9593

19186

28779

38372

47965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15080

30160

45240

60320

75400

<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:

0.796

AC:

121089

AN:

152200

Hom.:

48316

Cov.:

AF XY:

0.794

AC XY:

59062

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.851

AC:

35360

AN:

41542

American (AMR)

AF:

0.743

AC:

11352

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.794

AC:

2758

AN:

3472

East Asian (EAS)

AF:

0.872

AC:

4522

AN:

5186

South Asian (SAS)

AF:

0.809

AC:

3902

AN:

4824

European-Finnish (FIN)

AF:

0.760

AC:

8037

AN:

10570

Middle Eastern (MID)

AF:

0.755

AC:

222

AN:

294

European-Non Finnish (NFE)

AF:

0.775

AC:

52724

AN:

68002

Other (OTH)

AF:

0.784

AC:

1656

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1284

2568

3853

5137

6421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.785

Hom.:

5506

Bravo

AF:

0.795

Asia WGS

AF:

0.850

AC:

2954

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.90

(source)

DANN

Benign

0.77

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over