4-83310866-G-C

Variant names:

• chr4-83310866-G-C
• rs12512551
• NM_001098540.3:c.698C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001098540.3(HPSE):​c.698C>G​(p.Ala233Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00391 in 1,613,302 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (31 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (209 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030927062).
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0803 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPSE	NM_001098540.3	MANE Select	c.698C>G	p.Ala233Gly	missense	Exon 5 of 12	NP_001092010.1	Q9Y251-1
	HPSE	NM_006665.6		c.698C>G	p.Ala233Gly	missense	Exon 6 of 13	NP_006656.2	Q9Y251-1
	HPSE	NM_001199830.1		c.524C>G	p.Ala175Gly	missense	Exon 4 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.698C>G	p.Ala233Gly	missense	Exon 5 of 12	ENSP00000308107.5	Q9Y251-1
	HPSE	ENST00000405413.6	TSL:1	c.698C>G	p.Ala233Gly	missense	Exon 6 of 13	ENSP00000384262.2	Q9Y251-1
	HPSE	ENST00000513463.1	TSL:1	c.524C>G	p.Ala175Gly	missense	Exon 4 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152108 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0449

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0143 AC: 3583 AN: 251126 AF XY: 0.0119

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.00369 AC: 5397 AN: 1461076 Hom.: 209 Cov.: 30 AF XY: 0.00372 AC XY: 2701 AN XY: 726902

African (AFR) AF: 0.000688 AC: 23 AN: 33444

American (AMR) AF: 0.0825 AC: 3685 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39696

South Asian (SAS) AF: 0.0128 AC: 1100 AN: 86192

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53408

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.000310 AC: 344 AN: 1111452

Other (OTH) AF: 0.00326 AC: 197 AN: 60360

GnomAD4 genome AF: 0.00596 AC: 907 AN: 152226 Hom.: 31 Cov.: 31 AF XY: 0.00630 AC XY: 469 AN XY: 74440

African (AFR) AF: 0.00188 AC: 78 AN: 41524

American (AMR) AF: 0.0451 AC: 689 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68018

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00159 Hom.: 2

Bravo AF: 0.00988

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0108 AC: 1308

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000492

EpiControl AF: 0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.30	T
Sift4G	Benign	0.34	T
Polyphen		0.98	D
Vest4		0.055
MPC		0.12
ClinPred		0.032	T
GERP RS		5.2
Varity_R		0.48
gMVP		0.55
Mutation Taster		=93/7	polymorphism (auto)

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: rs12512551; hg19: chr4-84232019;