rs140139732

Variant names:

• chr1-21828852-G-A
• rs140139732
• NM_005529.7:c.12220C>T

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.12220C>T​(p.Arg4074Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,551,072 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4074H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (13 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.08
• Publications: 6 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=0.021296978).
• BP6: Variant 1-21828852-G-A is Benign according to our data. Variant chr1-21828852-G-A is described in ClinVar as Benign. ClinVar VariationId is 447539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00296 (450/152238) while in subpopulation NFE AF = 0.00191 (130/67998). AF 95% confidence interval is 0.00164. There are 7 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.12220C>T	p.Arg4074Cys	missense	Exon 88 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.12223C>T	p.Arg4075Cys	missense	Exon 88 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.12220C>T	p.Arg4074Cys	missense	Exon 88 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000486901.1	TSL:2	n.1559C>T		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152120 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00337 AC: 525 AN: 155730 AF XY: 0.00307

Gnomad AFR exome AF: 0.000114

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000907

GnomAD4 exome AF: 0.00175 AC: 2447 AN: 1398834 Hom.: 13 Cov.: 33 AF XY: 0.00169 AC XY: 1169 AN XY: 690000

African (AFR) AF: 0.000190 AC: 6 AN: 31616

American (AMR) AF: 0.000336 AC: 12 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 30 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35768

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79262

European-Finnish (FIN) AF: 0.0252 AC: 1226 AN: 48570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00101 AC: 1085 AN: 1079084

Other (OTH) AF: 0.00148 AC: 86 AN: 57998

GnomAD4 genome AF: 0.00296 AC: 450 AN: 152238 Hom.: 7 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.000608

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00144 AC: 12

ExAC AF: 0.00111 AC: 112

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Connective tissue disorder (1)
-	-	1	HSPG2-related 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	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	-0.010	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.1
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.45
Sift	Benign	0.071	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.48
MVP		0.81
MPC		0.83
ClinPred		0.058	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.65
Mutation Taster		=98/2	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: rs140139732; hg19: chr1-22155345; COSMIC: COSV100760712; COSMIC: COSV100760712;