chr1-21876613-C-T

Variant names:

• chr1-21876613-C-T
• rs137904249
• NM_005529.7:c.2725G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005529.7(HSPG2):​c.2725G>A​(p.Gly909Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00125 in 1,614,206 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G909C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 5.58
• Publications: 12 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000794 (121/152322) while in subpopulation NFE AF = 0.0014 (95/68026). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 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.2725G>A	p.Gly909Ser	missense	Exon 22 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.2728G>A	p.Gly910Ser	missense	Exon 22 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.2725G>A	p.Gly909Ser	missense	Exon 22 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000728 AC: 183 AN: 251378 AF XY: 0.000692

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00129 AC: 1889 AN: 1461884 Hom.: 5 Cov.: 33 AF XY: 0.00127 AC XY: 923 AN XY: 727246

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00160 AC: 1784 AN: 1112006

Other (OTH) AF: 0.00118 AC: 71 AN: 60396

GnomAD4 genome AF: 0.000794 AC: 121 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74492

African (AFR) AF: 0.000289 AC: 12 AN: 41580

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000979 Hom.: 2

Bravo AF: 0.000922

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	-	Connective tissue disorder (1)
-	1	-	HSPG2-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Lethal Kniest-like syndrome (1)
-	1	-	Lethal Kniest-like syndrome;C4551479:Schwartz-Jampel syndrome type 1 (1)
-	1	-	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.00040	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.66
MPC		0.78
ClinPred		0.13	T
GERP RS		5.0
Varity_R		0.22
gMVP		0.74
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137904249; hg19: chr1-22203106;