1-21841723-C-T

Variant names:

• chr1-21841723-C-T
• rs7556412
• NM_005529.7:c.9194-50G>A

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.9194-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,609,232 control chromosomes in the GnomAD database, including 338,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29305 hom., cov: 32)
  • Exomes 𝑓: 0.65 (309524 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.104
• Publications: 15 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=-0.8).
• BP6: Variant 1-21841723-C-T is Benign according to our data. Variant chr1-21841723-C-T is described in ClinVar as [Benign]. Clinvar id is 1231634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.9194-50G>A		intron_variant	Intron 69 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.9194-50G>A		intron_variant	Intron 69 of 96	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93525 AN: 151872 Hom.: 29274 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.625

GnomAD2 exomes AF: 0.652 AC: 161199 AN: 247280 AF XY: 0.653

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.718

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.691

Gnomad NFE exome AF: 0.658

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.650 AC: 947649 AN: 1457242 Hom.: 309524 Cov.: 34 AF XY: 0.650 AC XY: 471097 AN XY: 724932

African (AFR) AF: 0.502 AC: 16774 AN: 33396

American (AMR) AF: 0.614 AC: 27289 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 18784 AN: 26122

East Asian (EAS) AF: 0.835 AC: 33112 AN: 39664

South Asian (SAS) AF: 0.595 AC: 51116 AN: 85950

European-Finnish (FIN) AF: 0.685 AC: 36271 AN: 52958

Middle Eastern (MID) AF: 0.671 AC: 3513 AN: 5238

European-Non Finnish (NFE) AF: 0.650 AC: 721323 AN: 1109264

Other (OTH) AF: 0.655 AC: 39467 AN: 60234

GnomAD4 genome AF: 0.616 AC: 93610 AN: 151990 Hom.: 29305 Cov.: 32 AF XY: 0.619 AC XY: 45946 AN XY: 74282

African (AFR) AF: 0.506 AC: 20953 AN: 41426

American (AMR) AF: 0.593 AC: 9063 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2543 AN: 3472

East Asian (EAS) AF: 0.819 AC: 4225 AN: 5158

South Asian (SAS) AF: 0.612 AC: 2939 AN: 4806

European-Finnish (FIN) AF: 0.693 AC: 7324 AN: 10572

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44607 AN: 67952

Other (OTH) AF: 0.627 AC: 1323 AN: 2110

Alfa AF: 0.648 Hom.: 36500

Bravo AF: 0.609

Asia WGS AF: 0.734 AC: 2548 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	-0.80
CADD	Benign	1.8
DANN	Benign	0.76
PhyloP100		-0.10
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: rs7556412; hg19: chr1-22168216;