chr1-21888152-C-A

Position:

• chr1-21888152-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.575-86G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,573,620 control chromosomes in the GnomAD database, including 49,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5634 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43495 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.241

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]

HSPG2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-21888152-C-A is Benign according to our data. Variant chr1-21888152-C-A is described in ClinVar as [Benign]. Clinvar id is 1268753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.575-86G>T		intron_variant		ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.575-86G>T		intron_variant		1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000374673.4	c.380-86G>T		intron_variant		3		ENSP00000497688.1
HSPG2	ENST00000412328.5	n.343-86G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39169 AN: 152004 Hom.: 5633 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.254

GnomAD4 exome AF: 0.237 AC: 336498 AN: 1421498 Hom.: 43495 AF XY: 0.236 AC XY: 166674 AN XY: 707414

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.424

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.554

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.258 AC: 39191 AN: 152122 Hom.: 5634 Cov.: 32 AF XY: 0.262 AC XY: 19503 AN XY: 74382

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.253

Alfa AF: 0.229 Hom.: 498

Bravo AF: 0.266

Asia WGS AF: 0.372 AC: 1295 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.62

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: rs3767140; hg19: chr1-22214645;