dbSNP rs766419951: HPSE:p.Gly389Glu (chr4-83306243-C-T) – 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.1166G>A(p.Gly389Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,461,228 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

HPSE
NM_001098540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.05

Publications

2 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, 0.932

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.1166G>A	p.Gly389Glu	missense	Exon 9 of 12	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6		c.1166G>A	p.Gly389Glu	missense	Exon 10 of 13	NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1		c.992G>A	p.Gly331Glu	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.1166G>A	p.Gly389Glu	missense	Exon 9 of 12	ENSP00000308107.5	Q9Y251-1
HPSE	ENST00000405413.6	TSL:1	c.1166G>A	p.Gly389Glu	missense	Exon 10 of 13	ENSP00000384262.2	Q9Y251-1
HPSE	ENST00000513463.1	TSL:1	c.992G>A	p.Gly331Glu	missense	Exon 8 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461228

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111422

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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.:

Alfa

AF:

0.0000329

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.5

PhyloP100

7.1

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.98

MutPred

0.78

Gain of solvent accessibility (P = 0.0145)

MVP

0.46

MPC

0.50

ClinPred

0.99

GERP RS

4.8

Varity_R

0.93

gMVP

0.90

Mutation Taster

=6/94

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