NM_005529.7:c.4601C>G

Variant names:

• chr1-21864868-G-C
• rs142736845
• NM_005529.7:c.4601C>G

Variant summary

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

The NM_005529.7(HSPG2):​c.4601C>G​(p.Pro1534Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00161 in 1,610,498 control chromosomes in the GnomAD database, including 7 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 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 3.73
• Publications: 7 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105682105).
• BP6: Variant 1-21864868-G-C is Benign according to our data. Variant chr1-21864868-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287524.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00131 (199/152348) while in subpopulation AMR AF = 0.00268 (41/15310). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.4601C>G	p.Pro1534Arg	missense	Exon 36 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.4604C>G	p.Pro1535Arg	missense	Exon 36 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.4601C>G	p.Pro1534Arg	missense	Exon 36 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00135 AC: 316 AN: 233886 AF XY: 0.00131

Gnomad AFR exome AF: 0.000346

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.000867

GnomAD4 exome AF: 0.00164 AC: 2394 AN: 1458150 Hom.: 7 Cov.: 31 AF XY: 0.00155 AC XY: 1125 AN XY: 725210

African (AFR) AF: 0.000389 AC: 13 AN: 33428

American (AMR) AF: 0.00258 AC: 115 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 75 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000816 AC: 7 AN: 85784

European-Finnish (FIN) AF: 0.00105 AC: 54 AN: 51398

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00181 AC: 2006 AN: 1111276

Other (OTH) AF: 0.00196 AC: 118 AN: 60226

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74498

African (AFR) AF: 0.000457 AC: 19 AN: 41590

American (AMR) AF: 0.00268 AC: 41 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00170

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00199 AC: 17

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	-	Connective tissue disorder (1)
-	-	1	HSPG2-related disorder (1)
-	1	-	Lethal Kniest-like syndrome (1)
-	-	1	Multiple congenital anomalies/dysmorphic syndrome (1)
-	1	-	not specified (1)
-	1	-	Schwartz-Jampel syndrome (1)
-	1	-	Schwartz-Jampel syndrome;C1857100:Lethal Kniest-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.71
MPC		0.77
ClinPred		0.041	T
GERP RS		3.4
Varity_R		0.30
gMVP		0.43
Mutation Taster		=69/31	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: rs142736845; hg19: chr1-22191361; COSMIC: COSV108228426; COSMIC: COSV108228426;