Genetic Variant HPSE:p.Phe398Val (chr4-83306217-A-C) – 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.1192T>G(p.Phe398Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000829 in 1,447,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F398L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.33

Publications

0 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: 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, 0.903

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.1192T>G	p.Phe398Val	missense	Exon 9 of 12	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6		c.1192T>G	p.Phe398Val	missense	Exon 10 of 13	NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1		c.1018T>G	p.Phe340Val	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.1192T>G	p.Phe398Val	missense	Exon 9 of 12	ENSP00000308107.5	Q9Y251-1
HPSE	ENST00000405413.6	TSL:1	c.1192T>G	p.Phe398Val	missense	Exon 10 of 13	ENSP00000384262.2	Q9Y251-1
HPSE	ENST00000513463.1	TSL:1	c.1018T>G	p.Phe340Val	missense	Exon 8 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000829

AC:

AN:

1447788

Hom.:

Cov.:

AF XY:

0.00000970

AC XY:

AN XY:

721396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33226

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

85994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1099146

Other (OTH)

AF:

0.00

AC:

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.71

MutationAssessor

Pathogenic

3.4

PhyloP100

6.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.25

Sift

Benign

0.059

Sift4G

Benign

0.075

Polyphen

0.94

Vest4

0.84

MutPred

0.72

Gain of sheet (P = 0.1208)

MVP

0.44

MPC

0.43

ClinPred

0.98

GERP RS

4.7

Varity_R

0.66

gMVP

0.68

Mutation Taster

=45/55

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