rs142433309

Variant names:

• chr1-21861796-G-A
• rs142433309
• NM_005529.7:c.4916C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001291860.2(HSPG2):​c.4919C>T​(p.Thr1640Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,613,756 control chromosomes in the GnomAD database, including 15 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 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: HSPG2 NM_001291860.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 9.14
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16673473).
• BP6: Variant 1-21861796-G-A is Benign according to our data. Variant chr1-21861796-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197080.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0017 (259/152308) while in subpopulation NFE AF = 0.00271 (184/68020). AF 95% confidence interval is 0.00239. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291860.2. 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.4916C>T	p.Thr1639Met	missense	Exon 39 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.4919C>T	p.Thr1640Met	missense	Exon 39 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.4916C>T	p.Thr1639Met	missense	Exon 39 of 97	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00150 AC: 376 AN: 249944 AF XY: 0.00140

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00316 AC: 4623 AN: 1461448 Hom.: 14 Cov.: 32 AF XY: 0.00294 AC XY: 2141 AN XY: 727058

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00388 AC: 4310 AN: 1111950

Other (OTH) AF: 0.00321 AC: 194 AN: 60380

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74476

African (AFR) AF: 0.000842 AC: 35 AN: 41564

American (AMR) AF: 0.00235 AC: 36 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00271 AC: 184 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00227 Hom.: 7

Bravo AF: 0.00204

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00132 AC: 160

EpiCase AF: 0.00300

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	1	2	Schwartz-Jampel syndrome (3)
-	-	1	HSPG2-related disorder (1)
-	-	1	Intellectual disability (1)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.028	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.81
MPC		0.79
ClinPred		0.12	T
GERP RS		5.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.19
gMVP		0.41
Mutation Taster		=87/13	polymorphism

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: rs142433309; hg19: chr1-22188289;