rs16900528

chr5-83537572-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004385.5(VCAN):c.4569A>G(p.Thr1523=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,613,190 control chromosomes in the GnomAD database, including 5,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (448 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5383 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.102

Genes affected

VCAN (HGNC:2464): (versican) This gene is a member of the aggrecan/versican proteoglycan family. The protein encoded is a large chondroitin sulfate proteoglycan and is a major component of the extracellular matrix. This protein is involved in cell adhesion, proliferation, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance. Mutations in this gene are the cause of Wagner syndrome type 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

VCAN-AS1 (HGNC:40163): (VCAN antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-83537572-A-G is Benign according to our data. Variant chr5-83537572-A-G is described in ClinVar as [Benign]. Clinvar id is 259366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83537572-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCAN	NM_004385.5	c.4569A>G	p.Thr1523=	synonymous_variant	8/15	ENST00000265077.8
VCAN-AS1	NR_136215.1	n.285-3399T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCAN	ENST00000265077.8	c.4569A>G	p.Thr1523=	synonymous_variant	8/15	1	NM_004385.5

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10448 AN: 152112 Hom.: 448 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.0570

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0887

Gnomad OTH AF: 0.0741

GnomAD3 exomes AF: 0.0769 AC: 19217 AN: 249858 Hom.: 845 AF XY: 0.0789 AC XY: 10653 AN XY: 135012

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.0545

Gnomad SAS exome AF: 0.0897

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0895

Gnomad OTH exome AF: 0.0791

GnomAD4 exome AF: 0.0834 AC: 121802 AN: 1460960 Hom.: 5383 Cov.: 72 AF XY: 0.0838 AC XY: 60878 AN XY: 726792

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0447

Gnomad4 ASJ exome AF: 0.0634

Gnomad4 EAS exome AF: 0.0524

Gnomad4 SAS exome AF: 0.0910

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0868

Gnomad4 OTH exome AF: 0.0810

GnomAD4 genome AF: 0.0686 AC: 10450 AN: 152230 Hom.: 448 Cov.: 32 AF XY: 0.0700 AC XY: 5207 AN XY: 74426

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.0569

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.0570

Gnomad4 SAS AF: 0.0954

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0887

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0772 Hom.: 271

Bravo AF: 0.0596

Asia WGS AF: 0.104 AC: 361 AN: 3478

EpiCase AF: 0.0824

EpiControl AF: 0.0829

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wagner syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Vitreoretinopathy Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.2
Dann	Benign	0.66

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: rs16900528; hg19: chr5-82833391; COSMIC: COSV54104747; COSMIC: COSV54104747;