chr4-83300988-G-C

Variant names:

• chr4-83300988-G-C
• rs532481270
• NM_001098540.3:c.1444C>G

Variant summary

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

The NM_001098540.3(HPSE):​c.1444C>G​(p.Pro482Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000055 in 1,454,456 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

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 rank	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.1444C>G	p.Pro482Ala	missense_variant	Exon 11 of 12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.1444C>G	p.Pro482Ala	missense_variant	Exon 12 of 13		NP_006656.2
HPSE	NM_001199830.1	c.1270C>G	p.Pro424Ala	missense_variant	Exon 10 of 11		NP_001186759.1
HPSE	NM_001166498.3	c.1222C>G	p.Pro408Ala	missense_variant	Exon 10 of 11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.1444C>G	p.Pro482Ala	missense_variant	Exon 11 of 12	1	NM_001098540.3	ENSP00000308107.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454456 Hom.: 0 Cov.: 28 AF XY: 0.00000691 AC XY: 5 AN XY: 723812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000722

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1444C>G (p.P482A) alteration is located in exon 12 (coding exon 11) of the HPSE gene. This alteration results from a C to G substitution at nucleotide position 1444, causing the proline (P) at amino acid position 482 to be replaced by an alanine (A). 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	Benign	0.20
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	.;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.65
MutPred		0.42		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;
MVP		0.39
MPC		0.38
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.58
gMVP		0.68

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: rs532481270; hg19: chr4-84222141;