4-83301080-G-C

Position:

• chr4-83301080-G-C

Variant summary

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

The NM_001098540.3(HPSE):​c.1352C>G​(p.Thr451Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

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, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.1352C>G	p.Thr451Ser	missense_variant	11/12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.1352C>G	p.Thr451Ser	missense_variant	12/13		NP_006656.2
HPSE	NM_001199830.1	c.1178C>G	p.Thr393Ser	missense_variant	10/11		NP_001186759.1
HPSE	NM_001166498.3	c.1130C>G	p.Thr377Ser	missense_variant	10/11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.1352C>G	p.Thr451Ser	missense_variant	11/12	1	NM_001098540.3	ENSP00000308107	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

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

Nov 02, 2023

The c.1352C>G (p.T451S) 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 1352, causing the threonine (T) at amino acid position 451 to be replaced by a serine (S). 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	0.44
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.0	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;T
Polyphen		1.0	D;D;.;.
Vest4		0.70
MutPred		0.64		Loss of methylation at K446 (P = 0.0965);Loss of methylation at K446 (P = 0.0965);.;.;
MVP		0.77
MPC		0.45
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.77
gMVP		0.69

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: chr4-84222233;