rs897474

Variant names:

• chr1-21894938-T-C
• rs897474
• NM_005529.7:c.244+984A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-21894938-T-C
• chr1-21894938-T-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.244+984A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 152,120 control chromosomes in the GnomAD database, including 23,893 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 0.54 (23893 hom., cov: 33)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 1 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.244+984A>G		intron_variant	Intron 3 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.244+984A>G		intron_variant	Intron 3 of 96	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000412328.5	n.181+984A>G		intron_variant	Intron 2 of 5	2
HSPG2	ENST00000439717.2	n.142+984A>G		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81439 AN: 152002 Hom.: 23889 Cov.: 33

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.757

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.574

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

GnomAD4 genome AF: 0.535 AC: 81460 AN: 152120 Hom.: 23893 Cov.: 33 AF XY: 0.534 AC XY: 39721 AN XY: 74386

African (AFR) AF: 0.305 AC: 12678 AN: 41502

American (AMR) AF: 0.486 AC: 7425 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 2629 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1914 AN: 5168

South Asian (SAS) AF: 0.616 AC: 2972 AN: 4824

European-Finnish (FIN) AF: 0.643 AC: 6817 AN: 10600

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45128 AN: 67944

Other (OTH) AF: 0.576 AC: 1216 AN: 2112

Alfa AF: 0.601 Hom.: 3591

Bravo AF: 0.516

Asia WGS AF: 0.504 AC: 1751 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.80
PhyloP100		-1.2
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: rs897474; hg19: chr1-22221431;