rs139794766

Variant names:

• chr1-21857382-G-A
• rs139794766
• NM_005529.7:c.5297C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS1

The NM_005529.7(HSPG2):​c.5297C>T​(p.Ala1766Val) variant causes a missense change. The variant allele was found at a frequency of 0.000464 in 1,613,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1766T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 5.39
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21857383-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2506375.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011281133).
• BP6: Variant 1-21857382-G-A is Benign according to our data. Variant chr1-21857382-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 295834.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000328 (50/152264) while in subpopulation SAS AF = 0.00249 (12/4824). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.5297C>T	p.Ala1766Val	missense	Exon 43 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.5300C>T	p.Ala1767Val	missense	Exon 43 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.5297C>T	p.Ala1766Val	missense	Exon 43 of 97	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000584 AC: 146 AN: 250104 AF XY: 0.000732

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000478 AC: 699 AN: 1461250 Hom.: 1 Cov.: 34 AF XY: 0.000552 AC XY: 401 AN XY: 726926

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000425 AC: 19 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00293 AC: 253 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52916

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5764

European-Non Finnish (NFE) AF: 0.000335 AC: 373 AN: 1111906

Other (OTH) AF: 0.000447 AC: 27 AN: 60388

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74440

African (AFR) AF: 0.000193 AC: 8 AN: 41534

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000515 Hom.: 0

Bravo AF: 0.000295

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000708 AC: 86

EpiCase AF: 0.000763

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Connective tissue disorder (1)
-	-	1	HSPG2-related disorder (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	0.084
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.043
Sift	Benign	0.18	T
Sift4G	Benign	0.70	T
Polyphen		0.77	P
Vest4		0.19
MVP		0.59
MPC		0.26
ClinPred		0.098	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.28
Mutation Taster		=93/7	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: rs139794766; hg19: chr1-22183875; COSMIC: COSV65970207; COSMIC: COSV65970207;