Genetic Variant HPSE:p.Thr451Ile (chr4-83301080-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001098540.3(HPSE):c.1352C>T(p.Thr451Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000437 in 1,600,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T451S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.71

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

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.1352C>T	p.Thr451Ile	missense	Exon 11 of 12	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6		c.1352C>T	p.Thr451Ile	missense	Exon 12 of 13	NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1		c.1178C>T	p.Thr393Ile	missense	Exon 10 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.1352C>T	p.Thr451Ile	missense	Exon 11 of 12	ENSP00000308107.5	Q9Y251-1
HPSE	ENST00000405413.6	TSL:1	c.1352C>T	p.Thr451Ile	missense	Exon 12 of 13	ENSP00000384262.2	Q9Y251-1
HPSE	ENST00000513463.1	TSL:1	c.1178C>T	p.Thr393Ile	missense	Exon 10 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

239578

AF XY:

0.00000771

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1448166

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32428

American (AMR)

AF:

0.00

AC:

AN:

42486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39296

South Asian (SAS)

AF:

0.00

AC:

AN:

84004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1105140

Other (OTH)

AF:

0.00

AC:

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000712

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.039

MutationAssessor

Pathogenic

3.2

PhyloP100

6.7

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.94

MutPred

0.61

Loss of ubiquitination at K446 (P = 0.0595)

MVP

0.79

MPC

0.48

ClinPred

0.99

GERP RS

4.6

Varity_R

0.87

gMVP

0.84

Mutation Taster

=21/79

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over