chr1-21823459-C-T

Variant names:

• chr1-21823459-C-T
• rs148788926
• NM_005529.7:c.13033G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_005529.7(HSPG2):​c.13033G>A​(p.Gly4345Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,595,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. G4345E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.83
• Publications: 4 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]

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020376325).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000427 (65/152146) while in subpopulation NFE AF = 0.000691 (47/68006). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.13033G>A	p.Gly4345Arg	missense	Exon 97 of 97	NP_005520.4
	LDLRAD2	NM_001013693.3	MANE Select	c.*1244C>T		3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
	HSPG2	NM_001291860.2		c.13036G>A	p.Gly4346Arg	missense	Exon 97 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.13033G>A	p.Gly4345Arg	missense	Exon 97 of 97	ENSP00000363827.3	P98160
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*1244C>T		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
	LDLRAD2	ENST00000543870.1	TSL:1	c.*219-451C>T		intron	N/A	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000478 AC: 105 AN: 219664 AF XY: 0.000463

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.000793

Gnomad OTH exome AF: 0.000536

GnomAD4 exome AF: 0.000354 AC: 511 AN: 1443630 Hom.: 1 Cov.: 36 AF XY: 0.000376 AC XY: 270 AN XY: 717824

African (AFR) AF: 0.0000300 AC: 1 AN: 33290

American (AMR) AF: 0.000115 AC: 5 AN: 43418

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 54 AN: 25914

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39162

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85098

European-Finnish (FIN) AF: 0.000436 AC: 19 AN: 43572

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000360 AC: 399 AN: 1107558

Other (OTH) AF: 0.000434 AC: 26 AN: 59860

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74320

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.000359

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000538 AC: 65

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	1	-	Lethal Kniest-like syndrome (1)
-	1	-	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.94	L
PhyloP100		2.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.92	T
Sift4G	Benign	0.19	T
Polyphen		0.047	B
Vest4		0.15
MutPred		0.68		Gain of methylation at G4345 (P = 0.0183)
MVP		0.54
MPC		0.27
ClinPred		0.037	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.61
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs148788926; hg19: chr1-22149952;