rs12404444

Variant names:

• chr1-21864440-G-A
• rs12404444
• NM_005529.7:c.4627-227C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005529.7(HSPG2):​c.4627-227C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,244 control chromosomes in the GnomAD database, including 1,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (1914 hom., cov: 32)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.267

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-21864440-G-A is Benign according to our data. Variant chr1-21864440-G-A is described in ClinVar as [Benign]. Clinvar id is 1293133.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.4627-227C>T		intron_variant	Intron 36 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.4627-227C>T		intron_variant	Intron 36 of 96	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22198 AN: 152126 Hom.: 1913 Cov.: 32

Gnomad AFR AF: 0.0742

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.146 AC: 22201 AN: 152244 Hom.: 1914 Cov.: 32 AF XY: 0.145 AC XY: 10775 AN XY: 74418

Gnomad4 AFR AF: 0.0741

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.0878

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.144

Alfa AF: 0.172 Hom.: 1356

Bravo AF: 0.140

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12404444; hg19: chr1-22190933;