rs149094407

chr1-21880115-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_005529.7(HSPG2):c.2335C>T(p.His779Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,114 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00087 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.76

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.08509627).
• BP6: Variant 1-21880115-G-A is Benign according to our data. Variant chr1-21880115-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr1-21880115-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000873 (133/152362) while in subpopulation NFE AF= 0.00162 (110/68034). AF 95% confidence interval is 0.00137. There are 1 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.2335C>T	p.His779Tyr	missense_variant	17/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.2335C>T	p.His779Tyr	missense_variant	17/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152244 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000887 AC: 223 AN: 251328 Hom.: 0 AF XY: 0.000795 AC XY: 108 AN XY: 135880

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00131 AC: 1914 AN: 1461752 Hom.: 0 Cov.: 30 AF XY: 0.00126 AC XY: 915 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000600

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152362 Hom.: 1 Cov.: 34 AF XY: 0.000805 AC XY: 60 AN XY: 74512

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00135 Hom.: 1

Bravo AF: 0.000922

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000939 AC: 114

EpiCase AF: 0.00109

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 779 of the HSPG2 protein (p.His779Tyr). This variant is present in population databases (rs149094407, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 295880). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Lethal Kniest-like syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 19, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Schwartz-Jampel syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Benign	0.038	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.19
MVP		0.53
MPC		0.24
ClinPred		0.048	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.35

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: rs149094407; hg19: chr1-22206608;