rs10883100

chr10-98459617-T-Achr10-98459617-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021828.5(HPSE2):c.1736A>T(p.Tyr579Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,613,592 control chromosomes in the GnomAD database, including 201,094 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21512 hom., cov: 32)
  • Exomes 𝑓: 0.49 (179582 hom.)
• Consequence: HPSE2 NM_021828.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.54

Genes affected

HPSE2 (HGNC:18374): (heparanase 2 (inactive)) This gene encodes a heparanase enzyme. The encoded protein is a endoglycosidase that degrades heparin sulfate proteoglycans located on the extracellular matrix and cell surface. This protein may be involved in biological processes involving remodeling of the extracellular matrix including angiogenesis and tumor progression. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.144491E-4).
• BP6: Variant 10-98459617-T-A is Benign according to our data. Variant chr10-98459617-T-A is described in ClinVar as [Benign]. Clinvar id is 802626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98459617-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPSE2	NM_021828.5	c.1736A>T	p.Tyr579Phe	missense_variant	12/12	ENST00000370552.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPSE2	ENST00000370552.8	c.1736A>T	p.Tyr579Phe	missense_variant	12/12	1	NM_021828.5	P1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80142 AN: 151876 Hom.: 21498 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.505 AC: 126889 AN: 251258 Hom.: 32407 AF XY: 0.499 AC XY: 67840 AN XY: 135858

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.540

Gnomad SAS exome AF: 0.444

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.494 AC: 721963 AN: 1461598 Hom.: 179582 Cov.: 53 AF XY: 0.492 AC XY: 357691 AN XY: 727110

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.565

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.475

Gnomad4 NFE exome AF: 0.487

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.528 AC: 80211 AN: 151994 Hom.: 21512 Cov.: 32 AF XY: 0.525 AC XY: 38984 AN XY: 74300

Gnomad4 AFR AF: 0.617

Gnomad4 AMR AF: 0.511

Gnomad4 ASJ AF: 0.660

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.449

Gnomad4 NFE AF: 0.488

Gnomad4 OTH AF: 0.547

Alfa AF: 0.509 Hom.: 15044

Bravo AF: 0.542

TwinsUK AF: 0.484 AC: 1795

ALSPAC AF: 0.498 AC: 1920

ESP6500AA AF: 0.621 AC: 2738

ESP6500EA AF: 0.487 AC: 4185

ExAC AF: 0.504 AC: 61157

Asia WGS AF: 0.526 AC: 1831 AN: 3478

EpiCase AF: 0.492

EpiControl AF: 0.490

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Urofacial syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	22
Dann	Benign	0.94
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T;T;T;T
MetaRNN	Benign	0.00011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	3.1e-8	P;P;P;P
PrimateAI	Pathogenic	0.83	D
REVEL	Benign	0.15
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010, 1.0	.;B;D;D
Vest4		0.24, 0.32, 0.51
MPC		0.15
ClinPred		0.037	T
GERP RS		5.3
Varity_R		0.19
gMVP		0.59

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

Other links and lift over

dbSNP: rs10883100; hg19: chr10-100219374; COSMIC: COSV65184036;