NM_005529.7:c.11352+25C>A

Variant names:

• chr1-21831627-G-T
• rs2270701
• NM_005529.7:c.11352+25C>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.11352+25C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,610,728 control chromosomes in the GnomAD database, including 28,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1896 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26298 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-21831627-G-T is Benign according to our data. Variant chr1-21831627-G-T is described in ClinVar as [Benign]. Clinvar id is 1261831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.11352+25C>A		intron_variant	Intron 82 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.11352+25C>A		intron_variant	Intron 82 of 96	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000635682.1	c.501+25C>A		intron_variant	Intron 5 of 8	5		ENSP00000489161.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22287 AN: 152046 Hom.: 1894 Cov.: 33

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.181 AC: 44064 AN: 243214 Hom.: 4359 AF XY: 0.190 AC XY: 25001 AN XY: 131562

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.158

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.185 AC: 269771 AN: 1458564 Hom.: 26298 Cov.: 36 AF XY: 0.188 AC XY: 136338 AN XY: 725388

Gnomad4 AFR exome AF: 0.0573

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.147 AC: 22298 AN: 152164 Hom.: 1896 Cov.: 33 AF XY: 0.150 AC XY: 11131 AN XY: 74380

Gnomad4 AFR AF: 0.0590

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.143

Alfa AF: 0.157 Hom.: 1875

Bravo AF: 0.134

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal Kniest-like syndrome Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Schwartz-Jampel syndrome Benign:1

Aug 10, 2021

Genome-Nilou Lab

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	-0.92
CADD	Benign	0.023
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2270701; hg19: chr1-22158120;