chr1-21929191-T-C

Variant names:

• chr1-21929191-T-C
• rs16826053
• NM_005529.7:c.63+7964A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005529.7(HSPG2):​c.63+7964A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 152,276 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.016 (88 hom., cov: 32)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005529.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.63+7964A>G		intron	N/A	NP_005520.4
	HSPG2	NM_001291860.2		c.63+7964A>G		intron	N/A	NP_001278789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.63+7964A>G		intron	N/A	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2428 AN: 152158 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0247

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.0129

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

GnomAD4 genome AF: 0.0159 AC: 2425 AN: 152276 Hom.: 88 Cov.: 32 AF XY: 0.0174 AC XY: 1297 AN XY: 74456

African (AFR) AF: 0.0114 AC: 472 AN: 41548

American (AMR) AF: 0.0246 AC: 376 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.170 AC: 879 AN: 5174

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00545 AC: 371 AN: 68026

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.0118 Hom.: 5

Bravo AF: 0.0183

Asia WGS AF: 0.100 AC: 345 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.67
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16826053; hg19: chr1-22255684;