rs33599

Variant names:

• chr5-83479085-A-G
• rs33599
• NM_004385.5:c.-6-4428A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004385.5(VCAN):​c.-6-4428A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 151,942 control chromosomes in the GnomAD database, including 32,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (32063 hom., cov: 30)
• Consequence: VCAN NM_004385.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.656
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Wagner disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.-6-4428A>G		intron_variant	Intron 1 of 14	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.-6-4428A>G		intron_variant	Intron 1 of 13		NP_001157569.1
VCAN	NM_001164098.2	c.-6-4428A>G		intron_variant	Intron 1 of 13		NP_001157570.1
VCAN	NM_001126336.3	c.-6-4428A>G		intron_variant	Intron 1 of 12		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.-6-4428A>G		intron_variant	Intron 1 of 14	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96438 AN: 151824 Hom.: 32054 Cov.: 30

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.635 AC: 96492 AN: 151942 Hom.: 32063 Cov.: 30 AF XY: 0.637 AC XY: 47295 AN XY: 74258

African (AFR) AF: 0.420 AC: 17378 AN: 41410

American (AMR) AF: 0.705 AC: 10754 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2617 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2975 AN: 5154

South Asian (SAS) AF: 0.718 AC: 3453 AN: 4810

European-Finnish (FIN) AF: 0.695 AC: 7340 AN: 10556

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49627 AN: 67962

Other (OTH) AF: 0.668 AC: 1411 AN: 2112

Alfa AF: 0.708 Hom.: 21100

Bravo AF: 0.626

Asia WGS AF: 0.663 AC: 2303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.40
DANN	Benign	0.35
PhyloP100		-0.66
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: rs33599; hg19: chr5-82774904;