rs139453864

Variant names:

• chr5-83542237-G-A
• rs139453864
• NM_004385.5:c.9234G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004385.5(VCAN):​c.9234G>A​(p.Glu3078Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,758 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.215
• 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-AS1 (HGNC:40163): (VCAN antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-83542237-G-A is Benign according to our data. Variant chr5-83542237-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.215 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00266 (405/152286) while in subpopulation NFE AF = 0.00407 (277/68022). AF 95% confidence interval is 0.00368. There are 2 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 405 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	NM_004385.5	MANE Select	c.9234G>A	p.Glu3078Glu	synonymous	Exon 8 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.6273G>A	p.Glu2091Glu	synonymous	Exon 7 of 14	NP_001157569.1
	VCAN	NM_001164098.2		c.4004-3300G>A		intron	N/A	NP_001157570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.9234G>A	p.Glu3078Glu	synonymous	Exon 8 of 15	ENSP00000265077.3
	VCAN	ENST00000343200.9	TSL:1	c.6273G>A	p.Glu2091Glu	synonymous	Exon 7 of 14	ENSP00000340062.5
	VCAN	ENST00000513016.5	TSL:1	n.6624G>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00297 AC: 742 AN: 249868 AF XY: 0.00320

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00327 AC: 4784 AN: 1461472 Hom.: 12 Cov.: 34 AF XY: 0.00342 AC XY: 2488 AN XY: 727046

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.00116 AC: 52 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00384 AC: 331 AN: 86256

European-Finnish (FIN) AF: 0.00151 AC: 80 AN: 53130

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5766

European-Non Finnish (NFE) AF: 0.00369 AC: 4103 AN: 1111922

Other (OTH) AF: 0.00275 AC: 166 AN: 60394

GnomAD4 genome AF: 0.00266 AC: 405 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74464

African (AFR) AF: 0.000577 AC: 24 AN: 41562

American (AMR) AF: 0.00118 AC: 18 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00407 AC: 277 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00284

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00498

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Wagner disease (2)
-	-	1	Vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.8
DANN	Benign	0.81
PhyloP100		0.21
Mutation Taster		=100/0	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: rs139453864; hg19: chr5-82838056; COSMIC: COSV105873542; COSMIC: COSV105873542;