rs897471

chr1-21864961-G-Achr1-21864961-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• 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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• 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: 107084 AN: 152058 Hom.: 38063 Cov.: 34

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.713

GnomAD3 exomes AF: 0.732 AC: 160466 AN: 219192 Hom.: 59344 AF XY: 0.724 AC XY: 86840 AN XY: 119962

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.892

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.735

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.718 AC: 1039393 AN: 1447012 Hom.: 375403 Cov.: 68 AF XY: 0.715 AC XY: 514172 AN XY: 719032

Gnomad4 AFR exome AF: 0.605

Gnomad4 AMR exome AF: 0.802

Gnomad4 ASJ exome AF: 0.738

Gnomad4 EAS exome AF: 0.888

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.720

GnomAD4 genome AF: 0.704 AC: 107117 AN: 152176 Hom.: 38067 Cov.: 34 AF XY: 0.706 AC XY: 52535 AN XY: 74382

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.772

Gnomad4 ASJ AF: 0.752

Gnomad4 EAS AF: 0.886

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.736

Gnomad4 NFE AF: 0.732

Gnomad4 OTH AF: 0.711

Alfa AF: 0.734 Hom.: 75360

Bravo AF: 0.704

TwinsUK AF: 0.705 AC: 2613

ALSPAC AF: 0.717 AC: 2762

ESP6500AA AF: 0.620 AC: 2716

ESP6500EA AF: 0.740 AC: 6349

ExAC AF: 0.706 AC: 84444

Asia WGS AF: 0.700 AC: 2434 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 28, 2019	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.0024
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.15
Sift	Benign	0.056	T
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.11
MPC		0.33
ClinPred		0.020	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.52

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: rs897471; hg19: chr1-22191454; COSMIC: COSV65969427; COSMIC: COSV65969427;