rs143736974

chr1-21879108-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):c.2357A>G(p.Asn786Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00694 in 1,614,212 control chromosomes in the GnomAD database, including 63 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 0.0061 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (58 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 5.19

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.012245119).
• BP6: Variant 1-21879108-T-C is Benign according to our data. Variant chr1-21879108-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209161.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=1}. Variant chr1-21879108-T-C is described in Lovd as [Likely_benign]. Variant chr1-21879108-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00607 (924/152340) while in subpopulation NFE AF= 0.00867 (590/68042). AF 95% confidence interval is 0.00809. There are 5 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.2357A>G	p.Asn786Ser	missense_variant	18/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.2357A>G	p.Asn786Ser	missense_variant	18/97	1	NM_005529.7	P1
HSPG2	ENST00000480900.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 923 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00621 AC: 1561 AN: 251436 Hom.: 12 AF XY: 0.00659 AC XY: 895 AN XY: 135902

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00826

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00703 AC: 10283 AN: 1461872 Hom.: 58 Cov.: 35 AF XY: 0.00709 AC XY: 5156 AN XY: 727240

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.00758

Gnomad4 OTH exome AF: 0.00677

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74488

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.00867

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00684 Hom.: 12

Bravo AF: 0.00457

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	This variant is associated with the following publications: (PMID: 25504735) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HSPG2: BP4, BS2 -

Schwartz-Jampel syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2015	This variant has been seen once in our laboratory in trans with another variant [T1639M] in a 37-year-old female with adult-onset myalgia, myotonia, intractable pain, stiffness, weakness, constipation. However, other individuals in our lab with this variant and additional HSPG2 variants (phase undetermined) have not had significant overlap with the syndrome, although if it predisposes to a milder adult-onset version, they may be too young for symptoms. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Lethal Kniest-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	0.75	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.25	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.61
MPC		0.18
ClinPred		0.057	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs143736974; hg19: chr1-22205601; COSMIC: COSV104687789; COSMIC: COSV104687789;