1-21839541-G-A

Variant names:

• chr1-21839541-G-A
• rs62642505
• NM_005529.7:c.9719C>T

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.9719C>T​(p.Ala3240Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,826 control chromosomes in the GnomAD database, including 34 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3240T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.104
• Publications: 6 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=0.0130499005).
• BP6: Variant 1-21839541-G-A is Benign according to our data. Variant chr1-21839541-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00725 (1104/152236) while in subpopulation AFR AF = 0.0241 (1000/41544). AF 95% confidence interval is 0.0228. There are 15 homozygotes in GnomAd4. There are 512 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.9719C>T	p.Ala3240Val	missense	Exon 73 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.9722C>T	p.Ala3241Val	missense	Exon 73 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.9719C>T	p.Ala3240Val	missense	Exon 73 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1108 AN: 152118 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00864

GnomAD2 exomes AF: 0.00228 AC: 569 AN: 249124 AF XY: 0.00170

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.000373

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00103 AC: 1512 AN: 1461590 Hom.: 19 Cov.: 33 AF XY: 0.000919 AC XY: 668 AN XY: 727094

African (AFR) AF: 0.0289 AC: 967 AN: 33466

American (AMR) AF: 0.00224 AC: 100 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53272

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5766

European-Non Finnish (NFE) AF: 0.000192 AC: 213 AN: 1111944

Other (OTH) AF: 0.00283 AC: 171 AN: 60350

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152236 Hom.: 15 Cov.: 32 AF XY: 0.00688 AC XY: 512 AN XY: 74416

African (AFR) AF: 0.0241 AC: 1000 AN: 41544

American (AMR) AF: 0.00386 AC: 59 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67998

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.00267 Hom.: 11

Bravo AF: 0.00835

ESP6500AA AF: 0.0270 AC: 119

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.1
DANN	Benign	0.87
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N
PhyloP100		0.10
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.034
Sift	Benign	0.30	T
Sift4G	Benign	0.48	T
Polyphen		0.090	B
Vest4		0.050
MVP		0.28
MPC		0.21
ClinPred		0.0019	T
GERP RS		-0.95
Varity_R		0.038
gMVP		0.17
Mutation Taster		=98/2	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: rs62642505; hg19: chr1-22166034;