rs11556201

Variant names:

• chr4-83310827-A-T
• rs11556201
• NM_001098540.3:c.737T>A

Variant summary

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

The NM_001098540.3(HPSE):​c.737T>A​(p.Phe246Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.28

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, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.737T>A	p.Phe246Tyr	missense_variant	Exon 5 of 12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.737T>A	p.Phe246Tyr	missense_variant	Exon 6 of 13		NP_006656.2
HPSE	NM_001199830.1	c.563T>A	p.Phe188Tyr	missense_variant	Exon 4 of 11		NP_001186759.1
HPSE	NM_001166498.3	c.737T>A	p.Phe246Tyr	missense_variant	Exon 6 of 11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.737T>A	p.Phe246Tyr	missense_variant	Exon 5 of 12	1	NM_001098540.3	ENSP00000308107.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.71	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.44	T;T;D;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.46	P;P;.;.
Vest4		0.69
MutPred		0.74		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;
MVP		0.11
MPC		0.13
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.66
gMVP		0.79

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: rs11556201; hg19: chr4-84231980;