chr4-83300988-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001098540.3(HPSE):​c.1444C>A​(p.Pro482Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,454,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.1444C>A	p.Pro482Thr	missense_variant	Exon 11 of 12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.1444C>A	p.Pro482Thr	missense_variant	Exon 12 of 13		NP_006656.2
HPSE	NM_001199830.1	c.1270C>A	p.Pro424Thr	missense_variant	Exon 10 of 11		NP_001186759.1
HPSE	NM_001166498.3	c.1222C>A	p.Pro408Thr	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>A	p.Pro482Thr	missense_variant	Exon 11 of 12	1	NM_001098540.3	ENSP00000308107.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454456 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.4	M;M;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.083	T;T;D;D
Sift4G	Benign	0.10	T;T;D;T
Polyphen		0.99	D;D;.;.
Vest4		0.81
MutPred		0.44		Loss of catalytic residue at P482 (P = 0.087);Loss of catalytic residue at P482 (P = 0.087);.;.;
MVP		0.40
MPC		0.48
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.61
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84222141;