4-83310056-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098540.3(HPSE):c.865G>C(p.Val289Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPSE	NM_001098540.3	c.865G>C	p.Val289Leu	missense_variant	6/12	ENST00000311412.10
HPSE	NM_006665.6	c.865G>C	p.Val289Leu	missense_variant	7/13
HPSE	NM_001199830.1	c.691G>C	p.Val231Leu	missense_variant	5/11
HPSE	NM_001166498.3	c.865G>C	p.Val289Leu	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPSE	ENST00000311412.10	c.865G>C	p.Val289Leu	missense_variant	6/12	1	NM_001098540.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458966 Hom.: 0 Cov.: 27 AF XY: 0.00000275 AC XY: 2 AN XY: 725998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.865G>C (p.V289L) alteration is located in exon 7 (coding exon 6) of the HPSE gene. This alteration results from a G to C substitution at nucleotide position 865, causing the valine (V) at amino acid position 289 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.032	D;D;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.96	D;D;.;.
Vest4		0.38
MutPred		0.82		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.25
MPC		0.38
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.59
gMVP		0.71

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: rs1736307630; hg19: chr4-84231209;