rs142939330

Variant names:

• chr1-21836877-C-T
• rs142939330
• NM_005529.7:c.10280G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005529.7(HSPG2):​c.10280G>A​(p.Arg3427Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,575,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3427W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: -1.24
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002858013).
• BP6: Variant 1-21836877-C-T is Benign according to our data. Variant chr1-21836877-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 295739.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00121 (184/152316) while in subpopulation AFR AF = 0.00226 (94/41576). AF 95% confidence interval is 0.00189. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.10280G>A	p.Arg3427Gln	missense	Exon 75 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.10283G>A	p.Arg3428Gln	missense	Exon 75 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.10280G>A	p.Arg3427Gln	missense	Exon 75 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000374676.4	TSL:3	c.182-1240G>A		intron	N/A	ENSP00000363808.5	H7BYA5
	HSPG2	ENST00000471322.2	TSL:5	n.41G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000901 AC: 168 AN: 186500 AF XY: 0.000793

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00664

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.000457 AC: 650 AN: 1423186 Hom.: 0 Cov.: 32 AF XY: 0.000446 AC XY: 314 AN XY: 704314

African (AFR) AF: 0.00285 AC: 93 AN: 32592

American (AMR) AF: 0.00127 AC: 50 AN: 39386

Ashkenazi Jewish (ASJ) AF: 0.00678 AC: 172 AN: 25374

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37658

South Asian (SAS) AF: 0.0000987 AC: 8 AN: 81084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49950

Middle Eastern (MID) AF: 0.00402 AC: 23 AN: 5720

European-Non Finnish (NFE) AF: 0.000213 AC: 233 AN: 1092488

Other (OTH) AF: 0.00119 AC: 70 AN: 58934

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74464

African (AFR) AF: 0.00226 AC: 94 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000953 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.000619 AC: 74

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	1	HSPG2-related disorder (1)
-	1	-	Lethal Kniest-like syndrome (1)
-	1	-	Lethal Kniest-like syndrome;C4551479:Schwartz-Jampel syndrome type 1 (1)
-	-	1	not specified (1)
-	1	-	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.50
DANN	Benign	0.90
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
PhyloP100		-1.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.021
Sift	Benign	0.40	T
Sift4G	Benign	0.39	T
Polyphen		0.018	B
Vest4		0.074
MVP		0.11
MPC		0.23
ClinPred		0.0027	T
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.012
gMVP		0.15
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142939330; hg19: chr1-22163370;