rs7355045

Variant names:

• chr1-21845965-T-C
• rs7355045
• NM_005529.7:c.8464+143A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-21845965-T-C
• chr1-21845965-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.8464+143A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 979,460 control chromosomes in the GnomAD database, including 317,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46024 hom., cov: 32)
  • Exomes 𝑓: 0.81 (271703 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-21845965-T-C is Benign according to our data. Variant chr1-21845965-T-C is described in ClinVar as [Benign]. Clinvar id is 1245045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.8464+143A>G		intron_variant	Intron 64 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.8464+143A>G		intron_variant	Intron 64 of 96	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000453796.1	n.*231A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117918 AN: 152070 Hom.: 45976 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.894

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.789

GnomAD4 exome AF: 0.809 AC: 669565 AN: 827274 Hom.: 271703 AF XY: 0.812 AC XY: 347087 AN XY: 427708

African (AFR) AF: 0.707 AC: 15026 AN: 21242

American (AMR) AF: 0.694 AC: 26576 AN: 38280

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 17111 AN: 19206

East Asian (EAS) AF: 0.839 AC: 29181 AN: 34788

South Asian (SAS) AF: 0.812 AC: 51411 AN: 63282

European-Finnish (FIN) AF: 0.816 AC: 29331 AN: 35928

Middle Eastern (MID) AF: 0.848 AC: 2430 AN: 2864

European-Non Finnish (NFE) AF: 0.815 AC: 466753 AN: 572356

Other (OTH) AF: 0.807 AC: 31746 AN: 39328

GnomAD4 genome AF: 0.776 AC: 118021 AN: 152186 Hom.: 46024 Cov.: 32 AF XY: 0.774 AC XY: 57595 AN XY: 74400

African (AFR) AF: 0.701 AC: 29077 AN: 41488

American (AMR) AF: 0.709 AC: 10852 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 3105 AN: 3472

East Asian (EAS) AF: 0.821 AC: 4247 AN: 5170

South Asian (SAS) AF: 0.821 AC: 3962 AN: 4828

European-Finnish (FIN) AF: 0.824 AC: 8741 AN: 10614

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55390 AN: 68000

Other (OTH) AF: 0.789 AC: 1669 AN: 2114

Alfa AF: 0.796 Hom.: 6001

Bravo AF: 0.766

Asia WGS AF: 0.828 AC: 2877 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

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	-0.90
CADD	Benign	5.7
DANN	Benign	0.24
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7355045; hg19: chr1-22172458; COSMIC: COSV65970143; COSMIC: COSV65970143;