rs3736360

Variant names:

• chr1-21823627-C-T
• rs3736360
• NM_005529.7:c.12992G>A

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.12992G>A​(p.Ser4331Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,611,800 control chromosomes in the GnomAD database, including 28,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S4331S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1950 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26424 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00900
• Publications: 30 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]

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040354222).
• BP6: Variant 1-21823627-C-T is Benign according to our data. Variant chr1-21823627-C-T is described in ClinVar as Benign. ClinVar VariationId is 295700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.12992G>A	p.Ser4331Asn	missense	Exon 96 of 97	NP_005520.4
	LDLRAD2	NM_001013693.3	MANE Select	c.*1412C>T		3_prime_UTR	Exon 5 of 5	NP_001013715.2
	HSPG2	NM_001291860.2		c.12995G>A	p.Ser4332Asn	missense	Exon 96 of 97	NP_001278789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.12992G>A	p.Ser4331Asn	missense	Exon 96 of 97	ENSP00000363827.3
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*1412C>T		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2
	LDLRAD2	ENST00000543870.1	TSL:1	c.*219-283C>T		intron	N/A	ENSP00000444097.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23259 AN: 152080 Hom.: 1950 Cov.: 33

Gnomad AFR AF: 0.0827

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.181 AC: 45512 AN: 250946 AF XY: 0.189

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.160

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.185 AC: 270255 AN: 1459600 Hom.: 26424 Cov.: 36 AF XY: 0.188 AC XY: 136605 AN XY: 726264

African (AFR) AF: 0.0820 AC: 2745 AN: 33466

American (AMR) AF: 0.128 AC: 5742 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4533 AN: 26130

East Asian (EAS) AF: 0.172 AC: 6810 AN: 39680

South Asian (SAS) AF: 0.282 AC: 24307 AN: 86210

European-Finnish (FIN) AF: 0.235 AC: 12480 AN: 53114

Middle Eastern (MID) AF: 0.133 AC: 769 AN: 5764

European-Non Finnish (NFE) AF: 0.182 AC: 201860 AN: 1110182

Other (OTH) AF: 0.182 AC: 11009 AN: 60340

GnomAD4 genome AF: 0.153 AC: 23267 AN: 152200 Hom.: 1950 Cov.: 33 AF XY: 0.156 AC XY: 11625 AN XY: 74408

African (AFR) AF: 0.0827 AC: 3437 AN: 41536

American (AMR) AF: 0.131 AC: 2004 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 609 AN: 3472

East Asian (EAS) AF: 0.166 AC: 860 AN: 5170

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4822

European-Finnish (FIN) AF: 0.241 AC: 2553 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11961 AN: 67976

Other (OTH) AF: 0.147 AC: 310 AN: 2108

Alfa AF: 0.168 Hom.: 7817

Bravo AF: 0.141

TwinsUK AF: 0.186 AC: 688

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.0869 AC: 383

ESP6500EA AF: 0.176 AC: 1515

ExAC AF: 0.184 AC: 22397

Asia WGS AF: 0.243 AC: 843 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.177

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Lethal Kniest-like syndrome (2)
-	-	2	Schwartz-Jampel syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.0090
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.12
Sift	Benign	0.68	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.10
MPC		0.19
ClinPred		0.0026	T
GERP RS		2.0
Varity_R		0.24
gMVP		0.29
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3736360; hg19: chr1-22150120; COSMIC: COSV60827612; COSMIC: COSV60827612;