4-83309466-T-C

Position:

• chr4-83309466-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.920A>G	p.Lys307Arg	missense_variant	7/12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.920A>G	p.Lys307Arg	missense_variant	8/13		NP_006656.2
HPSE	NM_001199830.1	c.746A>G	p.Lys249Arg	missense_variant	6/11		NP_001186759.1
HPSE	NM_001166498.3	c.920A>G	p.Lys307Arg	missense_variant	8/11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.920A>G	p.Lys307Arg	missense_variant	7/12	1	NM_001098540.3	ENSP00000308107.5

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

GnomAD3 exomes AF: 0.779 AC: 188705 AN: 242270 Hom.: 73820 AF XY: 0.781 AC XY: 102156 AN XY: 130842

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 SAS exome AF: 0.793

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

Gnomad4 AFR exome AF: 0.852

Gnomad4 AMR exome AF: 0.701

Gnomad4 ASJ exome AF: 0.796

Gnomad4 EAS exome AF: 0.846

Gnomad4 SAS exome AF: 0.787

Gnomad4 FIN exome AF: 0.764

Gnomad4 NFE exome AF: 0.776

Gnomad4 OTH exome AF: 0.786

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

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.743

Gnomad4 ASJ AF: 0.794

Gnomad4 EAS AF: 0.872

Gnomad4 SAS AF: 0.810

Gnomad4 FIN AF: 0.759

Gnomad4 NFE AF: 0.775

Gnomad4 OTH AF: 0.785

Alfa AF: 0.781 Hom.: 115708

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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 v4.3

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;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0075
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	.;T;T;T
MetaRNN	Benign	7.1e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0040	B;B;.;.
Vest4		0.021
MPC		0.075
ClinPred		0.0031	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.44

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

Publications

LitVar

Other links and lift over

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