4-83309466-T-C

Variant names:

• chr4-83309466-T-C
• rs11099592
• NM_001098540.3:c.920A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001098540.3(HPSE):​c.920A>G​(p.Lys307Arg) variant causes a missense change. The variant allele was found at a frequency of 0.78 in 1,573,576 control chromosomes in the GnomAD database, including 480,564 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.80 (48322 hom., cov: 32)
  • Exomes 𝑓: 0.78 (432242 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.00
• Publications: 58 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.067377E-7).
• BP6: Variant 4-83309466-T-C is Benign according to our data. Variant chr4-83309466-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060058.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPSE	NM_001098540.3	MANE Select	c.920A>G	p.Lys307Arg	missense	Exon 7 of 12	NP_001092010.1
	HPSE	NM_006665.6		c.920A>G	p.Lys307Arg	missense	Exon 8 of 13	NP_006656.2
	HPSE	NM_001199830.1		c.746A>G	p.Lys249Arg	missense	Exon 6 of 11	NP_001186759.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPSE	ENST00000311412.10	TSL:1 MANE Select	c.920A>G	p.Lys307Arg	missense	Exon 7 of 12	ENSP00000308107.5
	HPSE	ENST00000405413.6	TSL:1	c.920A>G	p.Lys307Arg	missense	Exon 8 of 13	ENSP00000384262.2
	HPSE	ENST00000513463.1	TSL:1	c.746A>G	p.Lys249Arg	missense	Exon 6 of 11	ENSP00000421365.1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 121011 AN: 152090 Hom.: 48289 Cov.: 32

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.784

GnomAD2 exomes AF: 0.779 AC: 188705 AN: 242270 AF XY: 0.781

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.793

Gnomad EAS exome AF: 0.869

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.776

Gnomad OTH exome AF: 0.767

GnomAD4 exome AF: 0.779 AC: 1106906 AN: 1421368 Hom.: 432242 Cov.: 28 AF XY: 0.779 AC XY: 552073 AN XY: 708566

African (AFR) AF: 0.852 AC: 27459 AN: 32212

American (AMR) AF: 0.701 AC: 29985 AN: 42748

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 20496 AN: 25764

East Asian (EAS) AF: 0.846 AC: 33119 AN: 39130

South Asian (SAS) AF: 0.787 AC: 64947 AN: 82530

European-Finnish (FIN) AF: 0.764 AC: 40715 AN: 53326

Middle Eastern (MID) AF: 0.778 AC: 4442 AN: 5708

European-Non Finnish (NFE) AF: 0.776 AC: 839392 AN: 1081010

Other (OTH) AF: 0.786 AC: 46351 AN: 58940

GnomAD4 genome AF: 0.796 AC: 121096 AN: 152208 Hom.: 48322 Cov.: 32 AF XY: 0.794 AC XY: 59065 AN XY: 74410

African (AFR) AF: 0.851 AC: 35369 AN: 41542

American (AMR) AF: 0.743 AC: 11345 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2758 AN: 3472

East Asian (EAS) AF: 0.872 AC: 4516 AN: 5180

South Asian (SAS) AF: 0.810 AC: 3908 AN: 4826

European-Finnish (FIN) AF: 0.759 AC: 8042 AN: 10596

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.775 AC: 52722 AN: 68004

Other (OTH) AF: 0.785 AC: 1657 AN: 2112

Alfa AF: 0.782 Hom.: 208850

Bravo AF: 0.795

TwinsUK AF: 0.780 AC: 2891

ALSPAC AF: 0.787 AC: 3032

ESP6500AA AF: 0.848 AC: 3733

ESP6500EA AF: 0.773 AC: 6646

ExAC AF: 0.784 AC: 95189

Asia WGS AF: 0.849 AC: 2946 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HPSE-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0075
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.11
Sift	Benign	0.37	T
Sift4G	Benign	0.46	T
Polyphen		0.0040	B
Vest4		0.021
MPC		0.075
ClinPred		0.0031	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.44
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs11099592; hg19: chr4-84230619; COSMIC: COSV60987881;