rs143736974

Variant names:

• chr1-21879108-T-C
• rs143736974
• NM_005529.7:c.2357A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.2357A>G​(p.Asn786Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00694 in 1,614,212 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (58 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 5.19
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012245119).
• BP6: Variant 1-21879108-T-C is Benign according to our data. Variant chr1-21879108-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209161.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00607 (924/152340) while in subpopulation NFE AF = 0.00867 (590/68042). AF 95% confidence interval is 0.00809. There are 5 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.2357A>G	p.Asn786Ser	missense	Exon 18 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.2360A>G	p.Asn787Ser	missense	Exon 18 of 97	NP_001278789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.2357A>G	p.Asn786Ser	missense	Exon 18 of 97	ENSP00000363827.3
	HSPG2	ENST00000480900.1	TSL:5	n.-34A>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 923 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00621 AC: 1561 AN: 251436 AF XY: 0.00659

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00826

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00703 AC: 10283 AN: 1461872 Hom.: 58 Cov.: 35 AF XY: 0.00709 AC XY: 5156 AN XY: 727240

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00765 AC: 200 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00289 AC: 249 AN: 86258

European-Finnish (FIN) AF: 0.0159 AC: 850 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00758 AC: 8432 AN: 1112000

Other (OTH) AF: 0.00677 AC: 409 AN: 60394

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74488

African (AFR) AF: 0.00127 AC: 53 AN: 41578

American (AMR) AF: 0.00458 AC: 70 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00867 AC: 590 AN: 68042

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00698 Hom.: 20

Bravo AF: 0.00457

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00723

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Schwartz-Jampel syndrome (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.25	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.61
MPC		0.18
ClinPred		0.057	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.28
Mutation Taster		=80/20	polymorphism

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: rs143736974; hg19: chr1-22205601; COSMIC: COSV104687789; COSMIC: COSV104687789;