Genetic Variant HPSE:p.Ala352Ala (chr4-83308880-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001098540.3(HPSE):c.1056G>A(p.Ala352Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,613,968 control chromosomes in the GnomAD database, including 556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.017 ( 26 hom., cov: 32)

Exomes 𝑓: 0.024 ( 530 hom. )

Consequence

HPSE
NM_001098540.3 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -4.31

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 4-83308880-C-T is Benign according to our data. Variant chr4-83308880-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3056339.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-4.31 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2633/152294) while in subpopulation NFE AF= 0.0273 (1859/68034). AF 95% confidence interval is 0.0263. There are 26 homozygotes in gnomad4. There are 1211 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3 link	c.1056G>A	p.Ala352Ala	synonymous_variant	Exon 8 of 12	ENST00000311412.10	NP_001092010.1	Q9Y251-1
HPSE	NM_006665.6 link	c.1056G>A	p.Ala352Ala	synonymous_variant	Exon 9 of 13		NP_006656.2	Q9Y251-1
HPSE	NM_001199830.1 link	c.882G>A	p.Ala294Ala	synonymous_variant	Exon 7 of 11		NP_001186759.1	Q9Y251-2
HPSE	NM_001166498.3 link	c.984+522G>A		intron_variant	Intron 8 of 10		NP_001159970.1	Q9Y251-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10 link	c.1056G>A	p.Ala352Ala	synonymous_variant	Exon 8 of 12	1	NM_001098540.3	ENSP00000308107.5		Q9Y251-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2637

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0202

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0167

AC:

4205

AN:

251432

Hom.:

AF XY:

0.0168

AC XY:

2285

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00294

Gnomad FIN exome

AF:

0.0171

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0243

AC:

35557

AN:

1461674

Hom.:

530

Cov.:

AF XY:

0.0239

AC XY:

17352

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00409

Gnomad4 AMR exome

AF:

0.0129

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00328

Gnomad4 FIN exome

AF:

0.0180

Gnomad4 NFE exome

AF:

0.0285

Gnomad4 OTH exome

AF:

0.0230

GnomAD4 genome

AF:

0.0173

AC:

2633

AN:

152294

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1211

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00414

Gnomad4 AMR

AF:

0.0168

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0202

Gnomad4 NFE

AF:

0.0273

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0225

Hom.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0294

EpiControl

AF:

0.0284

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HPSE-related disorder

Benign:1

Feb 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.059

DANN

Benign

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over