5-83471911-A-C

Variant names:

• chr5-83471911-A-C
• rs557823406
• NM_004385.5:c.-119A>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004385.5(VCAN):​c.-119A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 393,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: VCAN NM_004385.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.79

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=-0.82).
• BP6: Variant 5-83471911-A-C is Benign according to our data. Variant chr5-83471911-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 354385.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000348 (53/152138) while in subpopulation SAS AF= 0.00146 (7/4800). AF 95% confidence interval is 0.000684. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.-119A>C		5_prime_UTR_variant	Exon 1 of 15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.-119A>C		5_prime_UTR_variant	Exon 1 of 14		NP_001157569.1
VCAN	NM_001164098.2	c.-119A>C		5_prime_UTR_variant	Exon 1 of 14		NP_001157570.1
VCAN	NM_001126336.3	c.-119A>C		5_prime_UTR_variant	Exon 1 of 13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077	c.-119A>C		5_prime_UTR_variant	Exon 1 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000505 AC: 122 AN: 241544 Hom.: 0 Cov.: 0 AF XY: 0.000538 AC XY: 66 AN XY: 122656

Gnomad4 AFR exome AF: 0.000283

Gnomad4 AMR exome AF: 0.000275

Gnomad4 ASJ exome AF: 0.00759

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.000871

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74356

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000374

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Wagner syndrome Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vitreoretinopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	13
DANN	Benign	0.58

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: rs557823406; hg19: chr5-82767730;