4-83306206-T-A

Variant names:

• chr4-83306206-T-A
• rs765800808
• NM_001098540.3:c.1203A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001098540.3(HPSE):​c.1203A>T​(p.Leu401Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,426,136 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: 0.0000042 (0 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.441
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPSE	NM_001098540.3	MANE Select	c.1203A>T	p.Leu401Phe	missense	Exon 9 of 12	NP_001092010.1	Q9Y251-1
	HPSE	NM_006665.6		c.1203A>T	p.Leu401Phe	missense	Exon 10 of 13	NP_006656.2	Q9Y251-1
	HPSE	NM_001199830.1		c.1029A>T	p.Leu343Phe	missense	Exon 8 of 11	NP_001186759.1	Q9Y251-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPSE	ENST00000311412.10	TSL:1 MANE Select	c.1203A>T	p.Leu401Phe	missense	Exon 9 of 12	ENSP00000308107.5	Q9Y251-1
	HPSE	ENST00000405413.6	TSL:1	c.1203A>T	p.Leu401Phe	missense	Exon 10 of 13	ENSP00000384262.2	Q9Y251-1
	HPSE	ENST00000513463.1	TSL:1	c.1029A>T	p.Leu343Phe	missense	Exon 8 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251364 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1426136 Hom.: 0 Cov.: 25 AF XY: 0.00000421 AC XY: 3 AN XY: 712018

African (AFR) AF: 0.00 AC: 0 AN: 32792

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1079448

Other (OTH) AF: 0.00 AC: 0 AN: 59176

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-0.44
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.39
Sift	Benign	0.031	D
Sift4G	Benign	0.096	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.43		Gain of catalytic residue at D403 (P = 0.095)
MVP		0.24
MPC		0.20
ClinPred		0.85	D
GERP RS		-2.1
Varity_R		0.66
gMVP		0.59
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs765800808; hg19: chr4-84227359;