chr1-21822499-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_005529.7(HSPG2):c.*817G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 321,424 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 (★).

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 1 hom. )

Consequence

HSPG2
NM_005529.7 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.00

Publications

0 publications found

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:

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]

LDLRAD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000478 (69/144380) while in subpopulation SAS AF = 0.00744 (30/4030). AF 95% confidence interval is 0.00536. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005529.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSPG2	NM_005529.7	MANE Select	c.*817G>A	3_prime_UTR	Exon 97 of 97	NP_005520.4
LDLRAD2	NM_001013693.3	MANE Select	c.*284C>T	3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
HSPG2	NM_001291860.2		c.*817G>A	3_prime_UTR	Exon 97 of 97	NP_001278789.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.*817G>A	3_prime_UTR	Exon 97 of 97	ENSP00000363827.3	P98160
LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*284C>T	3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
LDLRAD2	ENST00000543870.1	TSL:1	c.*218+66C>T	intron	N/A	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes

AF:

0.000485

AC:

AN:

144240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000851

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00771

Gnomad FIN

AF:

0.000218

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000892

AC:

158

AN:

177044

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

105

AN XY:

96120

show subpopulations

African (AFR)

AF:

0.00136

AC:

AN:

5146

American (AMR)

AF:

0.000186

AC:

AN:

10770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3998

East Asian (EAS)

AF:

0.00

AC:

AN:

8470

South Asian (SAS)

AF:

0.00354

AC:

118

AN:

33304

European-Finnish (FIN)

AF:

0.000636

AC:

AN:

7864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

672

European-Non Finnish (NFE)

AF:

0.000153

AC:

AN:

97908

Other (OTH)

AF:

0.00123

AC:

AN:

8912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000478

AC:

AN:

144380

Hom.:

Cov.:

AF XY:

0.000612

AC XY:

AN XY:

70286

show subpopulations

African (AFR)

AF:

0.000849

AC:

AN:

40062

American (AMR)

AF:

0.00

AC:

AN:

14588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3366

East Asian (EAS)

AF:

0.00

AC:

AN:

4254

South Asian (SAS)

AF:

0.00744

AC:

AN:

4030

European-Finnish (FIN)

AF:

0.000218

AC:

AN:

9194

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65698

Other (OTH)

AF:

0.00

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000268

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lethal Kniest-like syndrome (1)

Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.9

(source)

DANN

Benign

0.64

PhyloP100

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over