rs3736358

Positions:

• chr1-21823667-G-A
• chr1-21823667-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_005529.7(HSPG2):​c.12952C>T​(p.Arg4318Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000558 in 1,613,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4318P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (2 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.73

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 -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.24220261).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000335 (51/152216) while in subpopulation AMR AF= 0.00288 (44/15304). AF 95% confidence interval is 0.0022. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.12952C>T	p.Arg4318Trp	missense_variant	96/97	ENST00000374695.8
LDLRAD2	NM_001013693.3	c.*1452G>A		3_prime_UTR_variant	5/5	ENST00000344642.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.12952C>T	p.Arg4318Trp	missense_variant	96/97	1	NM_005529.7	P1
LDLRAD2	ENST00000344642.7	c.*1452G>A		3_prime_UTR_variant	5/5	2	NM_001013693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250734 Hom.: 1 AF XY: 0.0000516 AC XY: 7 AN XY: 135644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461454 Hom.: 2 Cov.: 41 AF XY: 0.0000261 AC XY: 19 AN XY: 727042

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74424

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000245 Hom.: 398

ExAC AF: 0.0000330 AC: 4

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	Feb 22, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4318 of the HSPG2 protein (p.Arg4318Trp). This variant is present in population databases (rs3736358, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. 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: 447541). 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

Jul 05, 2017

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2021

The c.12952C>T (p.R4318W) alteration is located in exon 95 (coding exon 95) of the HSPG2 gene. This alteration results from a C to T substitution at nucleotide position 12952, causing the arginine (R) at amino acid position 4318 to be replaced by a tryptophan (W). The p.R4318W alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.29
MutPred		0.50		Loss of disorder (P = 0.0085);
MVP		0.84
MPC		0.48
ClinPred		0.24	T
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.40
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs3736358; hg19: chr1-22150160; COSMIC: COSV60829904; COSMIC: COSV60829904;