rs777795072

chr1-21859942-C-Achr1-21859942-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BS1_Supporting

The NM_005529.7(HSPG2):c.5075G>T(p.Gly1692Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000764 in 1,610,422 control chromosomes in the GnomAD database, including 1 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.31

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.29195523).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000789 (115/1458256) while in subpopulation AMR AF= 0.000652 (29/44454). AF 95% confidence interval is 0.000467. There are 1 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.5075G>T	p.Gly1692Val	missense_variant	41/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.5075G>T	p.Gly1692Val	missense_variant	41/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000955 AC: 23 AN: 240806 Hom.: 1 AF XY: 0.0000765 AC XY: 10 AN XY: 130636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000472

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: 0.0000461

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.0000789 AC: 115 AN: 1458256 Hom.: 1 Cov.: 33 AF XY: 0.0000786 AC XY: 57 AN XY: 725062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000652

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 01, 2022	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1692 of the HSPG2 protein (p.Gly1692Val). This variant is present in population databases (rs777795072, gnomAD 0.05%), 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: 585994). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.5075G>T (p.G1692V) alteration is located in exon 40 (coding exon 40) of the HSPG2 gene. This alteration results from a G to T substitution at nucleotide position 5075, causing the glycine (G) at amino acid position 1692 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.85	D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.16
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.43
MutPred		0.47		Loss of disorder (P = 0.0827);
MVP		0.55
MPC		0.63
ClinPred		0.23	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.47
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -23

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

Publications

LitVar

Other links and lift over

dbSNP: rs777795072; hg19: chr1-22186435;