NM_005529.7:c.*992C>T

Variant names:

• chr1-21822324-G-A
• rs1049675
• NM_005529.7:c.*992C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.*992C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 1,128,680 control chromosomes in the GnomAD database, including 1,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (123 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1403 hom.)
• Consequence: HSPG2 NM_005529.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.271
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-21822324-G-A is Benign according to our data. Variant chr1-21822324-G-A is described in ClinVar as Benign. ClinVar VariationId is 295680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0734 is higher than 0.05.

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.*992C>T		3_prime_UTR	Exon 97 of 97	NP_005520.4
	LDLRAD2	NM_001013693.3	MANE Select	c.*109G>A		3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
	HSPG2	NM_001291860.2		c.*992C>T		3_prime_UTR	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.*992C>T		3_prime_UTR	Exon 97 of 97	ENSP00000363827.3	P98160
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*109G>A		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
	LDLRAD2	ENST00000543870.1	TSL:1	c.*109G>A		3_prime_UTR	Exon 5 of 6	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5199 AN: 152208 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.00895

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0787

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0514

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0484 AC: 47304 AN: 976354 Hom.: 1403 Cov.: 13 AF XY: 0.0505 AC XY: 25405 AN XY: 502986

African (AFR) AF: 0.00786 AC: 188 AN: 23930

American (AMR) AF: 0.0229 AC: 895 AN: 39064

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 908 AN: 22352

East Asian (EAS) AF: 0.000111 AC: 4 AN: 36106

South Asian (SAS) AF: 0.0852 AC: 6275 AN: 73608

European-Finnish (FIN) AF: 0.0235 AC: 1110 AN: 47180

Middle Eastern (MID) AF: 0.0609 AC: 294 AN: 4830

European-Non Finnish (NFE) AF: 0.0520 AC: 35656 AN: 685148

Other (OTH) AF: 0.0447 AC: 1974 AN: 44136

GnomAD4 genome AF: 0.0342 AC: 5203 AN: 152326 Hom.: 123 Cov.: 33 AF XY: 0.0327 AC XY: 2434 AN XY: 74484

African (AFR) AF: 0.00890 AC: 370 AN: 41578

American (AMR) AF: 0.0305 AC: 467 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0800 AC: 386 AN: 4826

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0514 AC: 3494 AN: 68024

Other (OTH) AF: 0.0431 AC: 91 AN: 2112

Alfa AF: 0.0467 Hom.: 226

Bravo AF: 0.0323

Asia WGS AF: 0.0310 AC: 106 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.77
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1049675; hg19: chr1-22148817;