rs897471
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1
The NM_005529.7(HSPG2):c.4508C>T(p.Ala1503Val) variant causes a missense change. The variant allele was found at a frequency of 0.717 in 1,599,188 control chromosomes in the GnomAD database, including 413,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1503A) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.70 ( 38067 hom., cov: 34)
Exomes 𝑓: 0.72 ( 375403 hom. )
Consequence
HSPG2
NM_005529.7 missense
NM_005529.7 missense
Scores
4
14
Clinical Significance
Conservation
PhyloP100: 4.32
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HSPG2. . Gene score misZ 1.1367 (greater than the threshold 3.09). Trascript score misZ 3.3999 (greater than threshold 3.09). GenCC has associacion of gene with Silverman-Handmaker type dyssegmental dysplasia, Schwartz-Jampel syndrome type 1, Schwartz-Jampel syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=1.2454389E-6).
BP6
Variant 1-21864961-G-A is Benign according to our data. Variant chr1-21864961-G-A is described in ClinVar as [Benign]. Clinvar id is 291236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21864961-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSPG2 | NM_005529.7 | c.4508C>T | p.Ala1503Val | missense_variant | 36/97 | ENST00000374695.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSPG2 | ENST00000374695.8 | c.4508C>T | p.Ala1503Val | missense_variant | 36/97 | 1 | NM_005529.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.704 AC: 107084AN: 152058Hom.: 38063 Cov.: 34
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GnomAD3 exomes AF: 0.732 AC: 160466AN: 219192Hom.: 59344 AF XY: 0.724 AC XY: 86840AN XY: 119962
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GnomAD4 exome AF: 0.718 AC: 1039393AN: 1447012Hom.: 375403 Cov.: 68 AF XY: 0.715 AC XY: 514172AN XY: 719032
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GnomAD4 genome AF: 0.704 AC: 107117AN: 152176Hom.: 38067 Cov.: 34 AF XY: 0.706 AC XY: 52535AN XY: 74382
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Lethal Kniest-like syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Schwartz-Jampel syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 20, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
P
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at