4-83313106-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001098540.3(HPSE):c.673+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,576,334 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (31 hom.)
• Consequence: HPSE NM_001098540.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006639
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.447

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-83313106-G-T is Benign according to our data. Variant chr4-83313106-G-T is described in ClinVar as [Benign]. Clinvar id is 714087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPSE	NM_001098540.3	c.673+8C>A		splice_region_variant, intron_variant		ENST00000311412.10
HPSE	NM_001166498.3	c.673+8C>A		splice_region_variant, intron_variant
HPSE	NM_001199830.1	c.500-2216C>A		intron_variant
HPSE	NM_006665.6	c.673+8C>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPSE	ENST00000311412.10	c.673+8C>A		splice_region_variant, intron_variant		1	NM_001098540.3	P1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 539 AN: 152034 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00315 AC: 779 AN: 247364 Hom.: 3 AF XY: 0.00295 AC XY: 395 AN XY: 133768

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.00671

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00467

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00489 AC: 6960 AN: 1424184 Hom.: 31 Cov.: 26 AF XY: 0.00473 AC XY: 3359 AN XY: 710736

Gnomad4 AFR exome AF: 0.000707

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00712

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00188

Gnomad4 NFE exome AF: 0.00578

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152150 Hom.: 2 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74392

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00133

Gnomad4 NFE AF: 0.00518

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00410 Hom.: 1

Bravo AF: 0.00406

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.5
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs184961893; hg19: chr4-84234259;