1-21873961-G-T

Variant names:

• chr1-21873961-G-T
• rs113652076
• NM_005529.7:c.3707C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.3707C>A​(p.Ala1236Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,605,542 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. A1236V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 2.53
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023008376).
• BP6: Variant 1-21873961-G-T is Benign according to our data. Variant chr1-21873961-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447549.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00183 (279/152286) while in subpopulation NFE AF = 0.0036 (245/68002). AF 95% confidence interval is 0.00323. There are 1 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.3707C>A	p.Ala1236Glu	missense	Exon 29 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.3710C>A	p.Ala1237Glu	missense	Exon 29 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.3707C>A	p.Ala1236Glu	missense	Exon 29 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000427897.1	TSL:5	n.269C>A		non_coding_transcript_exon	Exon 3 of 5	ENSP00000397573.1	H0Y5A9

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00163 AC: 383 AN: 235252 AF XY: 0.00173

Gnomad AFR exome AF: 0.000475

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000255

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00276 AC: 4018 AN: 1453256 Hom.: 9 Cov.: 32 AF XY: 0.00272 AC XY: 1962 AN XY: 721772

African (AFR) AF: 0.000389 AC: 13 AN: 33384

American (AMR) AF: 0.000411 AC: 18 AN: 43762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.00151 AC: 127 AN: 84224

European-Finnish (FIN) AF: 0.000322 AC: 17 AN: 52858

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5682

European-Non Finnish (NFE) AF: 0.00337 AC: 3732 AN: 1107890

Other (OTH) AF: 0.00178 AC: 107 AN: 60072

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74462

African (AFR) AF: 0.000577 AC: 24 AN: 41566

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00360 AC: 245 AN: 68002

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00248 Hom.: 4

Bravo AF: 0.00171

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	1	Connective tissue disorder (1)
-	-	1	HSPG2-related disorder (1)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	Multiple congenital anomalies/dysmorphic syndrome (1)
-	-	1	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Benign	0.0051
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.77	P
Vest4		0.35
MVP		0.67
MPC		0.57
ClinPred		0.026	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.29
gMVP		0.21
Mutation Taster		=65/35	polymorphism

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: rs113652076; hg19: chr1-22200454;