chr1-21822324-G-A

Position:

chr1-21822324-G-A

Variant summary

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

The NM_005529.7(HSPG2):c.*992C>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 0.0465 in 1,128,680 control chromosomes in the GnomAD database, including 1,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 123 hom., cov: 33)

Exomes 𝑓: 0.048 ( 1403 hom. )

Consequence

HSPG2
NM_005529.7 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.271

Variant links:

Genes affected

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:

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-21822324-G-A is Benign according to our data. Variant chr1-21822324-G-A is described in ClinVar as [Benign]. Clinvar id is 295680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAD2	NM_001013693.3 linkuse as main transcript	c.*109G>A		3_prime_UTR_variant	5/5	ENST00000344642.7
HSPG2	NM_005529.7 linkuse as main transcript	c.*992C>T		3_prime_UTR_variant	97/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAD2	ENST00000344642.7 linkuse as main transcript	c.*109G>A		3_prime_UTR_variant	5/5	2	NM_001013693.3	P1
HSPG2	ENST00000374695.8 linkuse as main transcript	c.*992C>T		3_prime_UTR_variant	97/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes

AF:

0.0342

AC:

5199

AN:

152208

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00895

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.0375

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0787

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0514

Gnomad OTH

AF:

0.0435

GnomAD4 exome

AF:

0.0484

AC:

47304

AN:

976354

Hom.:

1403

Cov.:

AF XY:

0.0505

AC XY:

25405

AN XY:

502986

show subpopulations

Gnomad4 AFR exome

AF:

0.00786

Gnomad4 AMR exome

AF:

0.0229

Gnomad4 ASJ exome

AF:

0.0406

Gnomad4 EAS exome

AF:

0.000111

Gnomad4 SAS exome

AF:

0.0852

Gnomad4 FIN exome

AF:

0.0235

Gnomad4 NFE exome

AF:

0.0520

Gnomad4 OTH exome

AF:

0.0447

GnomAD4 genome

AF:

0.0342

AC:

5203

AN:

152326

Hom.:

123

Cov.:

AF XY:

0.0327

AC XY:

2434

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00890

Gnomad4 AMR

AF:

0.0305

Gnomad4 ASJ

AF:

0.0375

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0800

Gnomad4 FIN

AF:

0.0197

Gnomad4 NFE

AF:

0.0514

Gnomad4 OTH

AF:

0.0431

Alfa

AF:

0.0460

Hom.:

Bravo

AF:

0.0323

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lethal Kniest-like syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Schwartz-Jampel syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.7

DANN

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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