1-21888152-C-A

Variant names:

• chr1-21888152-C-A
• rs3767140
• NM_005529.7:c.575-86G>T

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.575-86G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,573,620 control chromosomes in the GnomAD database, including 49,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5634 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43495 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.241
• Publications: 8 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=-0.81).
• BP6: Variant 1-21888152-C-A is Benign according to our data. Variant chr1-21888152-C-A is described in ClinVar as Benign. ClinVar VariationId is 1268753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.575-86G>T		intron_variant	Intron 6 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.575-86G>T		intron_variant	Intron 6 of 96	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000374673.4	c.380-86G>T		intron_variant	Intron 4 of 6	3		ENSP00000497688.1
HSPG2	ENST00000412328.5	n.343-86G>T		intron_variant	Intron 3 of 5	2

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39169 AN: 152004 Hom.: 5633 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.254

GnomAD4 exome AF: 0.237 AC: 336498 AN: 1421498 Hom.: 43495 AF XY: 0.236 AC XY: 166674 AN XY: 707414

African (AFR) AF: 0.257 AC: 8426 AN: 32776

American (AMR) AF: 0.424 AC: 18265 AN: 43080

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3411 AN: 25704

East Asian (EAS) AF: 0.554 AC: 21737 AN: 39210

South Asian (SAS) AF: 0.253 AC: 21453 AN: 84676

European-Finnish (FIN) AF: 0.220 AC: 9734 AN: 44300

Middle Eastern (MID) AF: 0.188 AC: 794 AN: 4222

European-Non Finnish (NFE) AF: 0.219 AC: 238187 AN: 1088484

Other (OTH) AF: 0.245 AC: 14491 AN: 59046

GnomAD4 genome AF: 0.258 AC: 39191 AN: 152122 Hom.: 5634 Cov.: 32 AF XY: 0.262 AC XY: 19503 AN XY: 74382

African (AFR) AF: 0.262 AC: 10854 AN: 41492

American (AMR) AF: 0.361 AC: 5526 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 439 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3033 AN: 5160

South Asian (SAS) AF: 0.250 AC: 1204 AN: 4820

European-Finnish (FIN) AF: 0.215 AC: 2275 AN: 10594

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15056 AN: 67974

Other (OTH) AF: 0.253 AC: 534 AN: 2110

Alfa AF: 0.229 Hom.: 498

Bravo AF: 0.266

Asia WGS AF: 0.372 AC: 1295 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	-0.81
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3767140; hg19: chr1-22214645;