rs886060816

Variant names:

• chr5-83471955-A-G
• rs886060816
• NM_004385.5:c.-75A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004385.5(VCAN):​c.-75A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 391,780 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: VCAN NM_004385.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.735
• Publications: 1 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: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00172 (262/152260) while in subpopulation AFR AF = 0.00602 (250/41548). AF 95% confidence interval is 0.0054. There are 1 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 262 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004385.5. 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
	VCAN	NM_004385.5	MANE Select	c.-75A>G		5_prime_UTR	Exon 1 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.-75A>G		5_prime_UTR	Exon 1 of 14	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.-75A>G		5_prime_UTR	Exon 1 of 14	NP_001157570.1	P13611-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.-75A>G		5_prime_UTR	Exon 1 of 15	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.-75A>G		5_prime_UTR	Exon 1 of 14	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.-75A>G		5_prime_UTR	Exon 1 of 14	ENSP00000342768.4	P13611-3

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000209 AC: 50 AN: 239520 Hom.: 0 Cov.: 0 AF XY: 0.000156 AC XY: 19 AN XY: 121542

African (AFR) AF: 0.00626 AC: 44 AN: 7026

American (AMR) AF: 0.00 AC: 0 AN: 7192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9052

East Asian (EAS) AF: 0.00 AC: 0 AN: 22476

South Asian (SAS) AF: 0.00 AC: 0 AN: 2134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1280

European-Non Finnish (NFE) AF: 0.0000130 AC: 2 AN: 154342

Other (OTH) AF: 0.000251 AC: 4 AN: 15930

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74454

African (AFR) AF: 0.00602 AC: 250 AN: 41548

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00195

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Wagner disease (2)
-	1	-	Vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		0.73
PromoterAI		0.076	Neutral
Mutation Taster		=295/5	polymorphism

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: rs886060816; hg19: chr5-82767774;