rs3767137

Variant names:

• chr1-21834230-G-A
• rs3767137
• NM_005529.7:c.10721-305C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005529.7(HSPG2):​c.10721-305C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,132 control chromosomes in the GnomAD database, including 4,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (4446 hom., cov: 32)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Schwartz-Jampel syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-21834230-G-A is Benign according to our data. Variant chr1-21834230-G-A is described in ClinVar as Benign. ClinVar VariationId is 1257676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.10721-305C>T		intron_variant	Intron 77 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.10721-305C>T		intron_variant	Intron 77 of 96	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000471322.2	n.1076-305C>T		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36706 AN: 152014 Hom.: 4440 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.245

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.242 AC: 36745 AN: 152132 Hom.: 4446 Cov.: 32 AF XY: 0.240 AC XY: 17849 AN XY: 74378

African (AFR) AF: 0.229 AC: 9510 AN: 41506

American (AMR) AF: 0.195 AC: 2976 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 854 AN: 3470

East Asian (EAS) AF: 0.168 AC: 869 AN: 5164

South Asian (SAS) AF: 0.390 AC: 1879 AN: 4820

European-Finnish (FIN) AF: 0.274 AC: 2897 AN: 10588

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16970 AN: 67984

Other (OTH) AF: 0.245 AC: 518 AN: 2110

Alfa AF: 0.248 Hom.: 1106

Bravo AF: 0.233

Asia WGS AF: 0.289 AC: 1004 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.69
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3767137; hg19: chr1-22160723;