rs114223739

Variant names:

• chr1-21831710-C-T
• rs114223739
• NM_005529.7:c.11294G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005529.7(HSPG2):​c.11294G>A​(p.Ser3765Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000613 in 1,606,198 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.86
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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 (MetaRNN=0.00824362).
• BP6: Variant 1-21831710-C-T is Benign according to our data. Variant chr1-21831710-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 295721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00316 (481/152266) while in subpopulation AFR AF = 0.0106 (441/41530). AF 95% confidence interval is 0.0098. There are 2 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.11294G>A	p.Ser3765Asn	missense	Exon 82 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.11297G>A	p.Ser3766Asn	missense	Exon 82 of 97	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.11294G>A	p.Ser3765Asn	missense	Exon 82 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000635682.1	TSL:5	c.443G>A	p.Ser148Asn	missense	Exon 5 of 9	ENSP00000489161.1	A0A0U1RQT3

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152148 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000858 AC: 207 AN: 241266 AF XY: 0.000638

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000568

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.000517

GnomAD4 exome AF: 0.000347 AC: 504 AN: 1453932 Hom.: 3 Cov.: 34 AF XY: 0.000309 AC XY: 223 AN XY: 721900

African (AFR) AF: 0.0114 AC: 382 AN: 33380

American (AMR) AF: 0.000980 AC: 43 AN: 43892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.0000588 AC: 5 AN: 85090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5740

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107426

Other (OTH) AF: 0.00113 AC: 68 AN: 59996

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152266 Hom.: 2 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74448

African (AFR) AF: 0.0106 AC: 441 AN: 41530

American (AMR) AF: 0.00209 AC: 32 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000797 Hom.: 1

Bravo AF: 0.00370

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00105 AC: 128

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-1.4	N
PhyloP100		3.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.22
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.54
MPC		0.19
ClinPred		0.022	T
GERP RS		4.2
Varity_R		0.066
gMVP		0.33
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs114223739; hg19: chr1-22158203;