5-83581863-A-G

Position:

• chr5-83581863-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004385.5(VCAN):​c.*1429A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 151,892 control chromosomes in the GnomAD database, including 23,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (23495 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: VCAN NM_004385.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-83581863-A-G is Benign according to our data. Variant chr5-83581863-A-G is described in ClinVar as [Benign]. Clinvar id is 354492.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.*1429A>G		3_prime_UTR_variant	15/15	ENST00000265077.8	NP_004376.2
VCAN	NM_001126336.3	c.*1429A>G		3_prime_UTR_variant	13/13		NP_001119808.1
VCAN	NM_001164097.2	c.*1429A>G		3_prime_UTR_variant	14/14		NP_001157569.1
VCAN	NM_001164098.2	c.*1429A>G		3_prime_UTR_variant	14/14		NP_001157570.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.*1429A>G		3_prime_UTR_variant	15/15	1	NM_004385.5	ENSP00000265077
VCAN	ENST00000342785.8	c.*1429A>G		3_prime_UTR_variant	14/14	1		ENSP00000342768
VCAN	ENST00000343200.9	c.*1429A>G		3_prime_UTR_variant	14/14	1		ENSP00000340062

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83973 AN: 151774 Hom.: 23484 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.584

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.553 AC: 84020 AN: 151892 Hom.: 23495 Cov.: 32 AF XY: 0.554 AC XY: 41152 AN XY: 74226

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.613

Gnomad4 SAS AF: 0.574

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.588

Alfa AF: 0.537 Hom.: 2782

Bravo AF: 0.560

Asia WGS AF: 0.610 AC: 2114 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

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	- -

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	-0.87
CADD	Benign	8.7
DANN	Benign	0.64

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: rs11726; hg19: chr5-82877682; COSMIC: COSV54101269; COSMIC: COSV54101269;