rs897471

Variant names:

• chr1-21864961-G-A
• rs897471
• NM_005529.7:c.4508C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-21864961-G-A
• chr1-21864961-G-C
• chr1-21864961-G-T

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.4508C>T​(p.Ala1503Val) variant causes a missense change. The variant allele was found at a frequency of 0.717 in 1,599,188 control chromosomes in the GnomAD database, including 413,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1503A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.70 (38067 hom., cov: 34)
  • Exomes 𝑓: 0.72 (375403 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.32
• Publications: 43 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=1.2454389E-6).
• BP6: Variant 1-21864961-G-A is Benign according to our data. Variant chr1-21864961-G-A is described in ClinVar as Benign. ClinVar VariationId is 291236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 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.4508C>T	p.Ala1503Val	missense	Exon 36 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.4511C>T	p.Ala1504Val	missense	Exon 36 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.4508C>T	p.Ala1503Val	missense	Exon 36 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.704 AC: 107084 AN: 152058 Hom.: 38063 Cov.: 34

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.713

GnomAD2 exomes AF: 0.732 AC: 160466 AN: 219192 AF XY: 0.724

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.892

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.735

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.718 AC: 1039393 AN: 1447012 Hom.: 375403 Cov.: 68 AF XY: 0.715 AC XY: 514172 AN XY: 719032

African (AFR) AF: 0.605 AC: 20062 AN: 33172

American (AMR) AF: 0.802 AC: 34870 AN: 43484

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 19109 AN: 25876

East Asian (EAS) AF: 0.888 AC: 34640 AN: 39026

South Asian (SAS) AF: 0.575 AC: 48423 AN: 84266

European-Finnish (FIN) AF: 0.742 AC: 36246 AN: 48874

Middle Eastern (MID) AF: 0.735 AC: 4209 AN: 5728

European-Non Finnish (NFE) AF: 0.722 AC: 798794 AN: 1106770

Other (OTH) AF: 0.720 AC: 43040 AN: 59816

GnomAD4 genome AF: 0.704 AC: 107117 AN: 152176 Hom.: 38067 Cov.: 34 AF XY: 0.706 AC XY: 52535 AN XY: 74382

African (AFR) AF: 0.612 AC: 25423 AN: 41526

American (AMR) AF: 0.772 AC: 11806 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2611 AN: 3472

East Asian (EAS) AF: 0.886 AC: 4563 AN: 5152

South Asian (SAS) AF: 0.568 AC: 2739 AN: 4824

European-Finnish (FIN) AF: 0.736 AC: 7795 AN: 10596

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.732 AC: 49756 AN: 67984

Other (OTH) AF: 0.711 AC: 1503 AN: 2114

Alfa AF: 0.729 Hom.: 106370

Bravo AF: 0.704

TwinsUK AF: 0.705 AC: 2613

ALSPAC AF: 0.717 AC: 2762

ESP6500AA AF: 0.620 AC: 2716

ESP6500EA AF: 0.740 AC: 6349

ExAC AF: 0.706 AC: 84444

Asia WGS AF: 0.700 AC: 2434 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Lethal Kniest-like syndrome (2)
-	-	2	Schwartz-Jampel syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.0024
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.15
Sift	Benign	0.056	T
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.11
MPC		0.33
ClinPred		0.020	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.52
Mutation Taster		=88/12	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: rs897471; hg19: chr1-22191454; COSMIC: COSV65969427; COSMIC: COSV65969427;