rs138518139

Positions:

• chr1-21896225-T-A
• chr1-21896225-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_005529.7(HSPG2):​c.149A>T​(p.His50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 1.18

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009218067).
• BP6: Variant 1-21896225-T-A is Benign according to our data. Variant chr1-21896225-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373152.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000981 (149/151954) while in subpopulation AFR AF= 0.00345 (143/41428). AF 95% confidence interval is 0.00299. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.149A>T	p.His50Leu	missense_variant	2/97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.149A>T	p.His50Leu	missense_variant	2/97	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000412328.5	n.86A>T		non_coding_transcript_exon_variant	1/6	2
HSPG2	ENST00000439717.2	n.47A>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.000981 AC: 149 AN: 151836 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251468 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135908

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.000116

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46 AN XY: 727240

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000180

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000981 AC: 149 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.000956 AC XY: 71 AN XY: 74244

Gnomad4 AFR AF: 0.00345

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.00123

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2024	Variant summary: HSPG2 c.149A>T (p.His50Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 1606848 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database. This frequency is higher than the estimated maximum expected for a pathogenic variant in HSPG2 causing Schwartz Jampel Syndrome Type 1 (~0.00056), suggesting that the variant might be benign. To our knowledge, no occurrence of c.149A>T in individuals affected with Schwartz Jampel Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 373152). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, flagged submission	clinical testing	GeneDx	Nov 22, 2016	The H50L variant in the HSPG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports H50L was observed in 12/4406 (0.27%) alleles from individuals of African American background, indicating it may be a rare variant in this population. The H50L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret H50Las a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 04, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.079
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0050	B
Vest4		0.41
MVP		0.58
MPC		0.25
ClinPred		0.0079	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs138518139; hg19: chr1-22222718;