chr1-21841112-C-T

Variant names:

• chr1-21841112-C-T
• rs2228349
• NM_005529.7:c.9502G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.9502G>A​(p.Ala3168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,608,368 control chromosomes in the GnomAD database, including 6,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3168G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (860 hom., cov: 33)
  • Exomes 𝑓: 0.082 (5507 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.959
• Publications: 16 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, 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=0.002572894).
• BP6: Variant 1-21841112-C-T is Benign according to our data. Variant chr1-21841112-C-T is described in ClinVar as Benign. ClinVar VariationId is 295758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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.9502G>A	p.Ala3168Thr	missense	Exon 71 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.9505G>A	p.Ala3169Thr	missense	Exon 71 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.9502G>A	p.Ala3168Thr	missense	Exon 71 of 97	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14919 AN: 152172 Hom.: 859 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.0663

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.0738 AC: 17383 AN: 235514 AF XY: 0.0764

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0562

Gnomad EAS exome AF: 0.000228

Gnomad FIN exome AF: 0.0580

Gnomad NFE exome AF: 0.0788

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0824 AC: 119917 AN: 1456078 Hom.: 5507 Cov.: 33 AF XY: 0.0833 AC XY: 60331 AN XY: 724050

African (AFR) AF: 0.173 AC: 5786 AN: 33358

American (AMR) AF: 0.0431 AC: 1897 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 1461 AN: 25964

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39480

South Asian (SAS) AF: 0.116 AC: 9939 AN: 85612

European-Finnish (FIN) AF: 0.0597 AC: 3115 AN: 52162

Middle Eastern (MID) AF: 0.0996 AC: 570 AN: 5722

European-Non Finnish (NFE) AF: 0.0831 AC: 92252 AN: 1109738

Other (OTH) AF: 0.0813 AC: 4886 AN: 60076

GnomAD4 genome AF: 0.0981 AC: 14940 AN: 152290 Hom.: 860 Cov.: 33 AF XY: 0.0944 AC XY: 7029 AN XY: 74476

African (AFR) AF: 0.162 AC: 6745 AN: 41546

American (AMR) AF: 0.0663 AC: 1014 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.110 AC: 532 AN: 4832

European-Finnish (FIN) AF: 0.0560 AC: 595 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0804 AC: 5471 AN: 68018

Other (OTH) AF: 0.101 AC: 214 AN: 2114

Alfa AF: 0.0849 Hom.: 1637

Bravo AF: 0.0994

TwinsUK AF: 0.0930 AC: 345

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.158 AC: 693

ESP6500EA AF: 0.0755 AC: 648

ExAC AF: 0.0747 AC: 9041

Asia WGS AF: 0.0520 AC: 181 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Lethal Kniest-like syndrome (2)
-	-	2	Schwartz-Jampel syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.6
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
PhyloP100		0.96
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.27	T
Sift4G	Benign	0.19	T
Polyphen		0.0060	B
Vest4		0.043
MPC		0.21
ClinPred		0.0057	T
GERP RS		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.36
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228349; hg19: chr1-22167605;