rs372318754

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_005529.7(HSPG2):c.4488G>A(p.Thr1496Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,589,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

HSPG2
NM_005529.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.418

Publications

1 publications found

Variant links:

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

HSPG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 1-21864981-C-T is Benign according to our data. Variant chr1-21864981-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 295845.

BP7

Synonymous conserved (PhyloP=-0.418 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000985 (150/152358) while in subpopulation AMR AF = 0.00176 (27/15312). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAd4. There are 71 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.4488G>A	p.Thr1496Thr	synonymous	Exon 36 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.4491G>A	p.Thr1497Thr	synonymous	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.4488G>A	p.Thr1496Thr	synonymous	Exon 36 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

150

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000712

AC:

143

AN:

200724

AF XY:

0.000822

show subpopulations

Gnomad AFR exome

AF:

0.000255

Gnomad AMR exome

AF:

0.000981

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00174

GnomAD4 exome

AF:

0.00110

AC:

1576

AN:

1437516

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

786

AN XY:

713660

show subpopulations

African (AFR)

AF:

0.000243

AC:

AN:

32906

American (AMR)

AF:

0.000957

AC:

AN:

41802

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25686

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38252

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83166

European-Finnish (FIN)

AF:

0.0000207

AC:

AN:

48250

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00132

AC:

1455

AN:

1102236

Other (OTH)

AF:

0.00112

AC:

AN:

59560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

179

269

358

448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152358

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41594

American (AMR)

AF:

0.00176

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000996

Hom.:

Bravo

AF:

0.000914

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Connective tissue disorder (1)

Lethal Kniest-like syndrome (1)

not specified (1)

Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.039

(source)

DANN

Benign

0.57

PhyloP100

-0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over