1-21833550-C-T

Variant names:

• chr1-21833550-C-T
• rs2229493
• NM_005529.7:c.10895G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.10895G>A​(p.Arg3632Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,613,860 control chromosomes in the GnomAD database, including 6,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. R3632L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (925 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5609 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0570
• Publications: 19 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=0.0018043518).
• BP6: Variant 1-21833550-C-T is Benign according to our data. Variant chr1-21833550-C-T is described in ClinVar as Benign. ClinVar VariationId is 295727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

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.10895G>A	p.Arg3632Gln	missense	Exon 79 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.10898G>A	p.Arg3633Gln	missense	Exon 79 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.10895G>A	p.Arg3632Gln	missense	Exon 79 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000635682.1	TSL:5	c.26G>A	p.Arg9Gln	missense	Exon 1 of 9	ENSP00000489161.1	A0A0U1RQT3
	HSPG2	ENST00000471322.2	TSL:5	n.1250G>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15308 AN: 151934 Hom.: 924 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0561

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0757 AC: 19005 AN: 251202 AF XY: 0.0776

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.0566

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0593

Gnomad NFE exome AF: 0.0796

Gnomad OTH exome AF: 0.0794

GnomAD4 exome AF: 0.0826 AC: 120778 AN: 1461808 Hom.: 5609 Cov.: 33 AF XY: 0.0836 AC XY: 60766 AN XY: 727204

African (AFR) AF: 0.183 AC: 6133 AN: 33480

American (AMR) AF: 0.0439 AC: 1964 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1476 AN: 26134

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.116 AC: 10019 AN: 86256

European-Finnish (FIN) AF: 0.0598 AC: 3192 AN: 53394

Middle Eastern (MID) AF: 0.100 AC: 579 AN: 5766

European-Non Finnish (NFE) AF: 0.0831 AC: 92421 AN: 1111960

Other (OTH) AF: 0.0825 AC: 4982 AN: 60396

GnomAD4 genome AF: 0.101 AC: 15329 AN: 152052 Hom.: 925 Cov.: 33 AF XY: 0.0968 AC XY: 7194 AN XY: 74330

African (AFR) AF: 0.171 AC: 7106 AN: 41458

American (AMR) AF: 0.0678 AC: 1036 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5148

South Asian (SAS) AF: 0.110 AC: 529 AN: 4806

European-Finnish (FIN) AF: 0.0561 AC: 595 AN: 10598

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0805 AC: 5473 AN: 67968

Other (OTH) AF: 0.105 AC: 222 AN: 2110

Alfa AF: 0.0849 Hom.: 1828

Bravo AF: 0.103

TwinsUK AF: 0.0925 AC: 343

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.173 AC: 763

ESP6500EA AF: 0.0769 AC: 661

ExAC AF: 0.0792 AC: 9618

Asia WGS AF: 0.0530 AC: 182 AN: 3478

EpiCase AF: 0.0776

EpiControl AF: 0.0750

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Lethal Kniest-like syndrome (2)
-	-	2	Schwartz-Jampel syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
PhyloP100		0.057
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.053
Sift	Benign	0.40	T
Sift4G	Benign	0.11	T
Polyphen		0.091	B
Vest4		0.051
MPC		0.24
ClinPred		0.0015	T
GERP RS		-1.1
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.43
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2229493; hg19: chr1-22160043; COSMIC: COSV105928417; COSMIC: COSV105928417;