4-83301004-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001098540.3(HPSE):c.1428T>G(p.Asp476Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,609,760 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.607

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019448966).
• BP6: Variant 4-83301004-A-C is Benign according to our data. Variant chr4-83301004-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3045667.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPSE	NM_001098540.3	c.1428T>G	p.Asp476Glu	missense_variant	11/12	ENST00000311412.10
HPSE	NM_006665.6	c.1428T>G	p.Asp476Glu	missense_variant	12/13
HPSE	NM_001199830.1	c.1254T>G	p.Asp418Glu	missense_variant	10/11
HPSE	NM_001166498.3	c.1206T>G	p.Asp402Glu	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPSE	ENST00000311412.10	c.1428T>G	p.Asp476Glu	missense_variant	11/12	1	NM_001098540.3	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000789 AC: 197 AN: 249678 Hom.: 1 AF XY: 0.000755 AC XY: 102 AN XY: 135018

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000444

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00139 AC: 2019 AN: 1457560 Hom.: 3 Cov.: 28 AF XY: 0.00134 AC XY: 971 AN XY: 725382

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000405

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.000930

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.000713 AC XY: 53 AN XY: 74356

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00133 Hom.: 1

Bravo AF: 0.000744

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00137

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HPSE-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2022

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
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.3
Dann	Benign	0.89
DEOGEN2	Benign	0.38	T;T;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.76	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.84	L;L;.;.
MutationTaster	Benign	0.81	D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.095
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.70	T;T;T;T
Polyphen		0.014	B;B;.;.
Vest4		0.13
MutPred		0.41		Gain of ubiquitination at K477 (P = 0.1278);Gain of ubiquitination at K477 (P = 0.1278);.;.;
MVP		0.17
MPC		0.089
ClinPred		0.060	T
GERP RS		-2.4
Varity_R		0.29
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs145560091; hg19: chr4-84222157; COSMIC: COSV60987428;