Genetic Variant HSPG2:c.*593C>T (chr1-21822723-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005529.7(HSPG2):c.*593C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 165,528 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

HSPG2
NM_005529.7 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.851

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: Benign. The variant received -14 ACMG points.

BP4

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

BP6

Variant 1-21822723-G-A is Benign according to our data. Variant chr1-21822723-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 295688.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00131 (200/152156) while in subpopulation EAS AF = 0.0126 (65/5168). AF 95% confidence interval is 0.0101. There are 2 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.*593C>T	3_prime_UTR	Exon 97 of 97	NP_005520.4
LDLRAD2	NM_001013693.3	MANE Select	c.*508G>A	3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
HSPG2	NM_001291860.2		c.*593C>T	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.*593C>T	3_prime_UTR	Exon 97 of 97	ENSP00000363827.3	P98160
LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*508G>A	3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
LDLRAD2	ENST00000543870.1	TSL:1	c.*218+290G>A	intron	N/A	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

201

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0127

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.00120

AC:

AN:

13372

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

AN XY:

7082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

300

American (AMR)

AF:

0.000539

AC:

AN:

1854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

216

East Asian (EAS)

AF:

0.0102

AC:

AN:

490

South Asian (SAS)

AF:

0.00

AC:

AN:

1258

European-Finnish (FIN)

AF:

0.00708

AC:

AN:

424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000611

AC:

AN:

8188

Other (OTH)

AF:

0.00333

AC:

AN:

600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.593

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152156

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41492

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0126

AC:

AN:

5168

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

67972

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000953

Hom.:

Bravo

AF:

0.000578

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

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

6.8

(source)

DANN

Benign

0.72

PhyloP100

0.85

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

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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