chr1-21847474-G-A

Variant names:

• chr1-21847474-G-A
• rs142458572
• NM_005529.7:c.8044C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005529.7(HSPG2):​c.8044C>T​(p.Arg2682Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,880 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2682Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (13 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.15
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Schwartz-Jampel syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14647627).
• BP6: Variant 1-21847474-G-A is Benign according to our data. Variant chr1-21847474-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 295780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152318) while in subpopulation NFE AF = 0.00309 (210/68014). AF 95% confidence interval is 0.00275. There are 0 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.8044C>T	p.Arg2682Trp	missense	Exon 62 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.8047C>T	p.Arg2683Trp	missense	Exon 62 of 97	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.8044C>T	p.Arg2682Trp	missense	Exon 62 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000453796.1	TSL:2	n.289C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00174 AC: 437 AN: 251254 AF XY: 0.00177

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00267 AC: 3899 AN: 1461562 Hom.: 13 Cov.: 33 AF XY: 0.00270 AC XY: 1964 AN XY: 727098

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.00181 AC: 96 AN: 53106

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.00302 AC: 3361 AN: 1111998

Other (OTH) AF: 0.00293 AC: 177 AN: 60392

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74482

African (AFR) AF: 0.000361 AC: 15 AN: 41588

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00309 AC: 210 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00283 Hom.: 7

Bravo AF: 0.00179

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	Lethal Kniest-like syndrome;C4551479:Schwartz-Jampel syndrome type 1 (2)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.81
MPC		0.80
ClinPred		0.030	T
GERP RS		2.4
Varity_R		0.26
gMVP		0.43
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs142458572; hg19: chr1-22173967; COSMIC: COSV106111025; COSMIC: COSV106111025;