rs200225298

Variant names:

• chr1-21836970-G-A
• rs200225298
• NM_005529.7:c.10187C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.10187C>T​(p.Ala3396Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,554,222 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (4 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 2.71
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041508794).
• BP6: Variant 1-21836970-G-A is Benign according to our data. Variant chr1-21836970-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289408.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000401 (61/152228) while in subpopulation AMR AF = 0.000785 (12/15290). AF 95% confidence interval is 0.000457. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.10187C>T	p.Ala3396Val	missense	Exon 75 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.10190C>T	p.Ala3397Val	missense	Exon 75 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.10187C>T	p.Ala3396Val	missense	Exon 75 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000374676.4	TSL:3	c.182-1333C>T		intron	N/A	ENSP00000363808.5	H7BYA5
	HSPG2	ENST00000471322.2	TSL:5	n.-53C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000436 AC: 70 AN: 160388 AF XY: 0.000567

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000518

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000692

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000583 AC: 817 AN: 1401994 Hom.: 4 Cov.: 33 AF XY: 0.000607 AC XY: 420 AN XY: 691856

African (AFR) AF: 0.000126 AC: 4 AN: 31758

American (AMR) AF: 0.000554 AC: 20 AN: 36084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 36010

South Asian (SAS) AF: 0.000604 AC: 48 AN: 79446

European-Finnish (FIN) AF: 0.0000411 AC: 2 AN: 48618

Middle Eastern (MID) AF: 0.00562 AC: 32 AN: 5698

European-Non Finnish (NFE) AF: 0.000626 AC: 677 AN: 1080968

Other (OTH) AF: 0.000584 AC: 34 AN: 58198

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74366

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.000785 AC: 12 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68038

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.000250 AC: 28

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	Lethal Kniest-like syndrome (1)
-	1	-	not specified (1)
-	1	-	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N
PhyloP100		2.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.034
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.0050	B
Vest4		0.13
MVP		0.57
MPC		0.20
ClinPred		0.020	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.27
Mutation Taster		=96/4	polymorphism

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: rs200225298; hg19: chr1-22163463;