Genetic Variant HSPG2:c.9194-50G>A (chr1-21841723-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.9194-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,609,232 control chromosomes in the GnomAD database, including 338,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 29305 hom., cov: 32)

Exomes 𝑓: 0.65 ( 309524 hom. )

Consequence

HSPG2
NM_005529.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.104

Variant links:

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]

HSPG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-21841723-C-T is Benign according to our data. Variant chr1-21841723-C-T is described in ClinVar as [Benign]. Clinvar id is 1231634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.9194-50G>A		intron_variant	Intron 69 of 96	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.9194-50G>A		intron_variant	Intron 69 of 96	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.616

AC:

93525

AN:

151872

Hom.:

29274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.505

Gnomad AMI

AF:

0.467

Gnomad AMR

AF:

0.593

Gnomad ASJ

AF:

0.732

Gnomad EAS

AF:

0.819

Gnomad SAS

AF:

0.613

Gnomad FIN

AF:

0.693

Gnomad MID

AF:

0.709

Gnomad NFE

AF:

0.656

Gnomad OTH

AF:

0.625

GnomAD3 exomes

AF:

0.652

AC:

161199

AN:

247280

Hom.:

52926

AF XY:

0.653

AC XY:

87353

AN XY:

133812

show subpopulations

Gnomad AFR exome

AF:

0.501

Gnomad AMR exome

AF:

0.617

Gnomad ASJ exome

AF:

0.718

Gnomad EAS exome

AF:

0.815

Gnomad SAS exome

AF:

0.602

Gnomad FIN exome

AF:

0.691

Gnomad NFE exome

AF:

0.658

Gnomad OTH exome

AF:

0.646

GnomAD4 exome

AF:

0.650

AC:

947649

AN:

1457242

Hom.:

309524

Cov.:

AF XY:

0.650

AC XY:

471097

AN XY:

724932

show subpopulations

Gnomad4 AFR exome

AF:

0.502

Gnomad4 AMR exome

AF:

0.614

Gnomad4 ASJ exome

AF:

0.719

Gnomad4 EAS exome

AF:

0.835

Gnomad4 SAS exome

AF:

0.595

Gnomad4 FIN exome

AF:

0.685

Gnomad4 NFE exome

AF:

0.650

Gnomad4 OTH exome

AF:

0.655

GnomAD4 genome

AF:

0.616

AC:

93610

AN:

151990

Hom.:

29305

Cov.:

AF XY:

0.619

AC XY:

45946

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.506

Gnomad4 AMR

AF:

0.593

Gnomad4 ASJ

AF:

0.732

Gnomad4 EAS

AF:

0.819

Gnomad4 SAS

AF:

0.612

Gnomad4 FIN

AF:

0.693

Gnomad4 NFE

AF:

0.656

Gnomad4 OTH

AF:

0.627

Alfa

AF:

0.651

Hom.:

31442

Bravo

AF:

0.609

Asia WGS

AF:

0.734

AC:

2548

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.8

DANN

Benign

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over