rs140621959

Variant names:

• chr1-21885130-C-T
• rs140621959
• NM_005529.7:c.1238G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21885130-C-T
• chr1-21885130-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005529.7(HSPG2):​c.1238G>A​(p.Arg413Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,610,952 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R413W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (18 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.79
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005518347).
• BP6: Variant 1-21885130-C-T is Benign according to our data. Variant chr1-21885130-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 295896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00201 (306/152198) while in subpopulation SAS AF = 0.00725 (35/4830). AF 95% confidence interval is 0.00536. There are 1 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.1238G>A	p.Arg413Gln	missense	Exon 11 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.1238G>A	p.Arg413Gln	missense	Exon 11 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.1238G>A	p.Arg413Gln	missense	Exon 11 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 305 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00310 AC: 753 AN: 242628 AF XY: 0.00365

Gnomad AFR exome AF: 0.000401

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00124

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00471

GnomAD4 exome AF: 0.00264 AC: 3846 AN: 1458754 Hom.: 18 Cov.: 35 AF XY: 0.00284 AC XY: 2057 AN XY: 725396

African (AFR) AF: 0.000329 AC: 11 AN: 33442

American (AMR) AF: 0.000877 AC: 39 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00200 AC: 52 AN: 25956

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39644

South Asian (SAS) AF: 0.00749 AC: 644 AN: 86012

European-Finnish (FIN) AF: 0.00122 AC: 64 AN: 52618

Middle Eastern (MID) AF: 0.0147 AC: 84 AN: 5724

European-Non Finnish (NFE) AF: 0.00247 AC: 2747 AN: 1110606

Other (OTH) AF: 0.00335 AC: 202 AN: 60264

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74416

African (AFR) AF: 0.000289 AC: 12 AN: 41526

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4830

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00327 AC: 222 AN: 67992

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00166

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00357 AC: 433

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not provided (10)
-	-	2	Schwartz-Jampel syndrome (2)
-	-	1	HSPG2-related disorder (1)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.45
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N
PhyloP100		2.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.43
MPC		0.23
ClinPred		0.0021	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140621959; hg19: chr1-22211623;