rs141280063

Positions:

• chr1-21824146-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.12874G>A​(p.Glu4292Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000992 in 1,613,548 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (2 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 4.24

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]

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 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=0.019059807).
• BP6: Variant 1-21824146-C-T is Benign according to our data. Variant chr1-21824146-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199234.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=2}. Variant chr1-21824146-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00127 (193/152318) while in subpopulation NFE AF= 0.000956 (65/68018). AF 95% confidence interval is 0.000769. There are 0 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.12874G>A	p.Glu4292Lys	missense_variant	95/97	ENST00000374695.8	NP_005520.4
LDLRAD2	NM_001013693.3	c.*1931C>T		3_prime_UTR_variant	5/5	ENST00000344642.7	NP_001013715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.12874G>A	p.Glu4292Lys	missense_variant	95/97	1	NM_005529.7	ENSP00000363827	P1
LDLRAD2	ENST00000344642.7	c.*1931C>T		3_prime_UTR_variant	5/5	2	NM_001013693.3	ENSP00000340988	P1
HSPG2	ENST00000481644.1	n.121G>A		non_coding_transcript_exon_variant	1/2	2
HSPG2	ENST00000486901.1	n.2213G>A		non_coding_transcript_exon_variant	9/11	2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00139 AC: 348 AN: 249934 Hom.: 0 AF XY: 0.00137 AC XY: 185 AN XY: 135514

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00991

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000964 AC: 1408 AN: 1461230 Hom.: 2 Cov.: 32 AF XY: 0.000993 AC XY: 722 AN XY: 726928

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00920

Gnomad4 NFE exome AF: 0.000751

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00162 AC XY: 121 AN XY: 74494

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000800 Hom.: 1

Bravo AF: 0.000491

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00119 AC: 144

EpiCase AF: 0.000981

EpiControl AF: 0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	This variant is associated with the following publications: (PMID: 30753492, 25504735) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2019	The HSPG2 c.12874G>A; p.Glu4292Lys variant (rs141280063) is reported in the literature in an individual with idiopathic scoliosis (Baschal 2014), though, to our knowledge, it has not been described in association with a congenital skeletal dysplasia. This variant is found in the Finnish European population with an overall allele frequency of 0.98% (243/24858 alleles) in the Genome Aggregation Database. The glutamate at codon 4292 is weakly conserved and computational analyses (SIFT: tolerate, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Glu4292Lys variant is uncertain at this time. References: Baschal EE et al. Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis. G3 (Bethesda). 2014 Dec 12;5(2):167-74 -

Lethal Kniest-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

HSPG2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schwartz-Jampel syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.83	L
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.12	T
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.69
MPC		0.44
ClinPred		0.037	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141280063; hg19: chr1-22150639;