chr1-21839968-T-G

Position:

• chr1-21839968-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_005529.7(HSPG2):​c.9563A>C​(p.Gln3188Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q3188H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HSPG2. . Gene score misZ 1.1367 (greater than the threshold 3.09). Trascript score misZ 3.3999 (greater than threshold 3.09). GenCC has associacion of gene with Silverman-Handmaker type dyssegmental dysplasia, Schwartz-Jampel syndrome type 1, Schwartz-Jampel syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.9563A>C	p.Gln3188Pro	missense_variant	72/97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.9563A>C	p.Gln3188Pro	missense_variant	72/97	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251452 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461884 Hom.: 1 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Schwartz-Jampel syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.69		Gain of glycosylation at Q3188 (P = 0.0342);
MVP		0.74
MPC		0.71
ClinPred		0.57	D
GERP RS		4.4
Varity_R		0.88
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.82		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758584149; hg19: chr1-22166461;