rs75467696

Variant names:

• chr1-21885448-G-T
• rs75467696
• NM_005529.7:c.1082C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21885448-G-T
• chr1-21885448-G-A
• chr1-21885448-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005529.7(HSPG2):​c.1082C>A​(p.Thr361Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,613,976 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (41 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.55
• Publications: 7 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=0.009220779).
• BP6: Variant 1-21885448-G-T is Benign according to our data. Variant chr1-21885448-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00349 (531/152234) while in subpopulation NFE AF = 0.00578 (393/67990). AF 95% confidence interval is 0.00531. There are 0 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 41 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.1082C>A	p.Thr361Asn	missense	Exon 10 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.1082C>A	p.Thr361Asn	missense	Exon 10 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.1082C>A	p.Thr361Asn	missense	Exon 10 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00446 AC: 1120 AN: 251064 AF XY: 0.00460

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00692

Gnomad NFE exome AF: 0.00706

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00589 AC: 8610 AN: 1461742 Hom.: 41 Cov.: 33 AF XY: 0.00586 AC XY: 4258 AN XY: 727166

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00192 AC: 86 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00275 AC: 237 AN: 86252

European-Finnish (FIN) AF: 0.00658 AC: 351 AN: 53330

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00687 AC: 7636 AN: 1111982

Other (OTH) AF: 0.00437 AC: 264 AN: 60396

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00324 AC XY: 241 AN XY: 74430

African (AFR) AF: 0.000915 AC: 38 AN: 41548

American (AMR) AF: 0.00235 AC: 36 AN: 15302

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

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

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4820

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00578 AC: 393 AN: 67990

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00518 Hom.: 7

Bravo AF: 0.00334

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00512 AC: 622

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	0.083
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.090	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.069	T
Sift4G	Uncertain	0.019	D
Polyphen		0.61	P
Vest4		0.18
MVP		0.71
MPC		0.31
ClinPred		0.014	T
GERP RS		3.2
Varity_R		0.096
gMVP		0.31
Mutation Taster		=99/1	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: rs75467696; hg19: chr1-22211941;