NM_001098540.3:c.1056G>A

Variant names:

• chr4-83308880-C-T
• rs139839221
• NM_001098540.3:c.1056G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001098540.3(HPSE):​c.1056G>A​(p.Ala352Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,613,968 control chromosomes in the GnomAD database, including 556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (26 hom., cov: 32)
  • Exomes 𝑓: 0.024 (530 hom.)
• Consequence: HPSE NM_001098540.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.31
• Publications: 3 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 (BayesDel_noAF=-0.36).
• BP6: Variant 4-83308880-C-T is Benign according to our data. Variant chr4-83308880-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3056339.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-4.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2633/152294) while in subpopulation NFE AF = 0.0273 (1859/68034). AF 95% confidence interval is 0.0263. There are 26 homozygotes in GnomAd4. There are 1211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.1056G>A	p.Ala352Ala	synonymous	Exon 8 of 12	NP_001092010.1	Q9Y251-1
	HPSE	NM_006665.6		c.1056G>A	p.Ala352Ala	synonymous	Exon 9 of 13	NP_006656.2	Q9Y251-1
	HPSE	NM_001199830.1		c.882G>A	p.Ala294Ala	synonymous	Exon 7 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.1056G>A	p.Ala352Ala	synonymous	Exon 8 of 12	ENSP00000308107.5	Q9Y251-1
	HPSE	ENST00000405413.6	TSL:1	c.1056G>A	p.Ala352Ala	synonymous	Exon 9 of 13	ENSP00000384262.2	Q9Y251-1
	HPSE	ENST00000513463.1	TSL:1	c.882G>A	p.Ala294Ala	synonymous	Exon 7 of 11	ENSP00000421365.1	Q9Y251-2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2637 AN: 152176 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0167 AC: 4205 AN: 251432 AF XY: 0.0168

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0243 AC: 35557 AN: 1461674 Hom.: 530 Cov.: 31 AF XY: 0.0239 AC XY: 17352 AN XY: 727146

African (AFR) AF: 0.00409 AC: 137 AN: 33474

American (AMR) AF: 0.0129 AC: 578 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 327 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00328 AC: 283 AN: 86248

European-Finnish (FIN) AF: 0.0180 AC: 960 AN: 53420

Middle Eastern (MID) AF: 0.0343 AC: 197 AN: 5746

European-Non Finnish (NFE) AF: 0.0285 AC: 31688 AN: 1111844

Other (OTH) AF: 0.0230 AC: 1386 AN: 60382

GnomAD4 genome AF: 0.0173 AC: 2633 AN: 152294 Hom.: 26 Cov.: 32 AF XY: 0.0163 AC XY: 1211 AN XY: 74440

African (AFR) AF: 0.00414 AC: 172 AN: 41568

American (AMR) AF: 0.0168 AC: 257 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0202 AC: 214 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1859 AN: 68034

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0225 Hom.: 24

Bravo AF: 0.0173

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0294

EpiControl AF: 0.0284

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HPSE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.059
DANN	Benign	0.87
PhyloP100		-4.3
Mutation Taster		=100/0	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: rs139839221; hg19: chr4-84230033;