rs368983547

Positions:

• chr1-21864215-TA-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.4627-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,550,870 control chromosomes in the GnomAD database, including 17 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (17 hom.)
• Consequence: HSPG2 NM_005529.7 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: -0.103

Genes affected

HSPG2 (HGNC:5273): (heparan sulfate proteoglycan 2) This gene encodes the perlecan protein, which consists of a core protein to which three long chains of glycosaminoglycans (heparan sulfate or chondroitin sulfate) are attached. The perlecan protein is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix components and cell-surface molecules. It has been shown that this protein interacts with laminin, prolargin, collagen type IV, FGFBP1, FBLN2, FGF7 and transthyretin, etc., and it plays essential roles in multiple biological activities. Perlecan is a key component of the vascular extracellular matrix, where it helps to maintain the endothelial barrier function. It is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. It can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. It is a major component of basement membranes, where it is involved in the stabilization of other molecules as well as being involved with glomerular permeability to macromolecules and cell adhesion. Mutations in this gene cause Schwartz-Jampel syndrome type 1, Silverman-Handmaker type of dyssegmental dysplasia, and tardive dyskinesia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 1-21864215-TA-T is Benign according to our data. Variant chr1-21864215-TA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197010.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=3}. Variant chr1-21864215-TA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (293/152274) while in subpopulation NFE AF= 0.00287 (195/68010). AF 95% confidence interval is 0.00254. There are 0 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.4627-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.4627-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005529.7	ENSP00000363827	P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00226 AC: 355 AN: 156934 Hom.: 1 AF XY: 0.00223 AC XY: 184 AN XY: 82658

Gnomad AFR exome AF: 0.000227

Gnomad AMR exome AF: 0.000886

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00202

Gnomad FIN exome AF: 0.00565

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00203

GnomAD4 exome AF: 0.00300 AC: 4193 AN: 1398596 Hom.: 17 Cov.: 31 AF XY: 0.00296 AC XY: 2040 AN XY: 689906

Gnomad4 AFR exome AF: 0.000380

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00597

Gnomad4 NFE exome AF: 0.00330

Gnomad4 OTH exome AF: 0.00216

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74452

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00287

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00170

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	HSPG2: BP4, BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2020	- -

Lethal Kniest-like syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2020

The c.4627-3delT alteration is located 3 nucleotides before coding exon 36 of the HSPG2 gene. This alteration results from a deletion of nucleotide at nucleotide position c.4627-3. Based on data from the Genome Aggregation Database (gnomAD) database, the HSPG2 c.4627-3delT alteration was observed in 0.22% (422/188312) of total alleles studied, with a frequency of 0.52% (99/18868) in the European (Finnish) subpopulation. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Schwartz-Jampel syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs368983547; hg19: chr1-22190708;