rs199814977

chr1-21824762-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_Supporting

The NM_005529.7(HSPG2):c.12607G>A(p.Gly4203Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,612,988 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.20

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]

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.24817309).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000355 (54/152222) while in subpopulation AFR AF= 0.00125 (52/41460). AF 95% confidence interval is 0.000982. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.12607G>A	p.Gly4203Arg	missense_variant	92/97	ENST00000374695.8
LDLRAD2	NM_001013693.3	c.*2547C>T		3_prime_UTR_variant	5/5	ENST00000344642.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.12607G>A	p.Gly4203Arg	missense_variant	92/97	1	NM_005529.7	P1
LDLRAD2	ENST00000344642.7	c.*2547C>T		3_prime_UTR_variant	5/5	2	NM_001013693.3	P1
HSPG2	ENST00000486901.1	n.1946G>A		non_coding_transcript_exon_variant	6/11	2

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000105 AC: 26 AN: 247452 Hom.: 0 AF XY: 0.0000894 AC XY: 12 AN XY: 134202

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000466 AC: 68 AN: 1460766 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 726592

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74376

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4203 of the HSPG2 protein (p.Gly4203Arg). This variant is present in population databases (rs199814977, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 447540). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 08, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.12607G>A (p.G4203R) alteration is located in exon 91 (coding exon 91) of the HSPG2 gene. This alteration results from a G to A substitution at nucleotide position 12607, causing the glycine (G) at amino acid position 4203 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.56		Loss of catalytic residue at P4199 (P = 0.1103);
MVP		0.78
MPC		0.85
ClinPred		0.092	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199814977; hg19: chr1-22151255;