1-21889786-C-T

Variant names:

• chr1-21889786-C-T
• rs3767141
• NM_005529.7:c.574+195G>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.574+195G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 630,300 control chromosomes in the GnomAD database, including 31,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6637 hom., cov: 32)
  • Exomes 𝑓: 0.32 (25060 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72
• Publications: 11 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=-0.87).
• BP6: Variant 1-21889786-C-T is Benign according to our data. Variant chr1-21889786-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.574+195G>A		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.574+195G>A		intron_variant	Intron 6 of 96	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000374673.4	c.328+195G>A		intron_variant	Intron 3 of 6	3		ENSP00000497688.1
HSPG2	ENST00000412328.5	n.342+195G>A		intron_variant	Intron 3 of 5	2
HSPG2	ENST00000439717.2	n.*30G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42994 AN: 151900 Hom.: 6632 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.319 AC: 152376 AN: 478280 Hom.: 25060 Cov.: 5 AF XY: 0.318 AC XY: 79840 AN XY: 251378

African (AFR) AF: 0.170 AC: 2222 AN: 13080

American (AMR) AF: 0.450 AC: 9428 AN: 20938

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 3314 AN: 14174

East Asian (EAS) AF: 0.396 AC: 12321 AN: 31084

South Asian (SAS) AF: 0.317 AC: 14703 AN: 46386

European-Finnish (FIN) AF: 0.345 AC: 15263 AN: 44178

Middle Eastern (MID) AF: 0.270 AC: 962 AN: 3562

European-Non Finnish (NFE) AF: 0.310 AC: 86161 AN: 278048

Other (OTH) AF: 0.298 AC: 8002 AN: 26830

GnomAD4 genome AF: 0.283 AC: 43011 AN: 152020 Hom.: 6637 Cov.: 32 AF XY: 0.286 AC XY: 21235 AN XY: 74310

African (AFR) AF: 0.172 AC: 7143 AN: 41476

American (AMR) AF: 0.387 AC: 5902 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 785 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1954 AN: 5146

South Asian (SAS) AF: 0.298 AC: 1435 AN: 4818

European-Finnish (FIN) AF: 0.332 AC: 3503 AN: 10566

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21205 AN: 67956

Other (OTH) AF: 0.277 AC: 587 AN: 2116

Alfa AF: 0.296 Hom.: 11406

Bravo AF: 0.280

Asia WGS AF: 0.318 AC: 1108 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	-0.87
CADD	Benign	0.23
DANN	Benign	0.72
PhyloP100		-1.7
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: rs3767141; hg19: chr1-22216279; COSMIC: COSV107487800; COSMIC: COSV107487800;