rs145687082

Variant names:

• chr1-21823474-C-T
• rs145687082
• NM_005529.7:c.13018G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21823474-C-T
• chr1-21823474-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.13018G>A​(p.Val4340Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,599,730 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 2.20
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0090253055).
• BP6: Variant 1-21823474-C-T is Benign according to our data. Variant chr1-21823474-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 499443.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (161/152296) while in subpopulation NFE AF = 0.00149 (101/68008). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.13018G>A	p.Val4340Met	missense	Exon 97 of 97	NP_005520.4
	LDLRAD2	NM_001013693.3	MANE Select	c.*1259C>T		3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
	HSPG2	NM_001291860.2		c.13021G>A	p.Val4341Met	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.13018G>A	p.Val4340Met	missense	Exon 97 of 97	ENSP00000363827.3	P98160
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*1259C>T		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
	LDLRAD2	ENST00000543870.1	TSL:1	c.*219-436C>T		intron	N/A	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00132 AC: 298 AN: 225426 AF XY: 0.00131

Gnomad AFR exome AF: 0.000356

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000519

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00155 AC: 2245 AN: 1447434 Hom.: 5 Cov.: 36 AF XY: 0.00153 AC XY: 1102 AN XY: 719994

African (AFR) AF: 0.000210 AC: 7 AN: 33378

American (AMR) AF: 0.00137 AC: 60 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.0000770 AC: 2 AN: 25980

East Asian (EAS) AF: 0.000610 AC: 24 AN: 39366

South Asian (SAS) AF: 0.000656 AC: 56 AN: 85416

European-Finnish (FIN) AF: 0.00197 AC: 88 AN: 44736

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.00172 AC: 1904 AN: 1109126

Other (OTH) AF: 0.00165 AC: 99 AN: 59944

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00114 AC XY: 85 AN XY: 74454

African (AFR) AF: 0.000289 AC: 12 AN: 41574

American (AMR) AF: 0.000849 AC: 13 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00140 Hom.: 1

Bravo AF: 0.00105

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00154 AC: 186

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
-	2	4	not provided (6)
-	-	1	Connective tissue disorder (1)
-	-	1	HSPG2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Lethal Kniest-like syndrome (1)
-	1	-	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.27	N
PhyloP100		2.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.26
Sift	Benign	0.27	T
Sift4G	Benign	0.37	T
Polyphen		1.0	D
Vest4		0.13
MVP		0.62
MPC		0.47
ClinPred		0.011	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.23
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs145687082; hg19: chr1-22149967; COSMIC: COSV60828163; COSMIC: COSV60828163;