NM_004385.5:c.9075G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004385.5(VCAN):c.9075G>A(p.Thr3025Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,613,704 control chromosomes in the GnomAD database, including 1,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 87 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1130 hom. )

Consequence

VCAN
NM_004385.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.307

Publications

7 publications found

Variant links:

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 links:

VCAN-AS1 (HGNC:40163): (VCAN antisense RNA 1)

VCAN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 5-83542078-G-A is Benign according to our data. Variant chr5-83542078-G-A is described in ClinVar as Benign. ClinVar VariationId is 259375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.307 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0276 (4203/152248) while in subpopulation NFE AF = 0.0387 (2635/68014). AF 95% confidence interval is 0.0375. There are 87 homozygotes in GnomAd4. There are 2020 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5 link	c.9075G>A	p.Thr3025Thr	synonymous_variant	Exon 8 of 15	ENST00000265077.8	NP_004376.2	P13611-1A0A024RAQ9Q59FG9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8 link	c.9075G>A	p.Thr3025Thr	synonymous_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3		P13611-1

Frequencies

GnomAD3 genomes

AF:

0.0277

AC:

4207

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00702

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0859

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.0315

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0388

Gnomad OTH

AF:

0.0350

GnomAD2 exomes

AF:

0.0305

AC:

7655

AN:

250712

AF XY:

0.0314

show subpopulations

Gnomad AFR exome

AF:

0.00628

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0791

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0331

Gnomad NFE exome

AF:

0.0412

Gnomad OTH exome

AF:

0.0435

GnomAD4 exome

AF:

0.0359

AC:

52450

AN:

1461456

Hom.:

1130

Cov.:

AF XY:

0.0356

AC XY:

25883

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.00666

AC:

223

AN:

33470

American (AMR)

AF:

0.0222

AC:

992

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0800

AC:

2090

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39686

South Asian (SAS)

AF:

0.0138

AC:

1192

AN:

86254

European-Finnish (FIN)

AF:

0.0314

AC:

1677

AN:

53412

Middle Eastern (MID)

AF:

0.0404

AC:

233

AN:

5764

European-Non Finnish (NFE)

AF:

0.0395

AC:

43911

AN:

1111638

Other (OTH)

AF:

0.0352

AC:

2126

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3190

6379

9569

12758

15948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1566

3132

4698

6264

7830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0276

AC:

4203

AN:

152248

Hom.:

Cov.:

AF XY:

0.0271

AC XY:

2020

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00700

AC:

291

AN:

41562

American (AMR)

AF:

0.0304

AC:

465

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0859

AC:

298

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0147

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0315

AC:

334

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0387

AC:

2635

AN:

68014

Other (OTH)

AF:

0.0346

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

210

420

631

841

1051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0377

Hom.:

Bravo

AF:

0.0265

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0444

EpiControl

AF:

0.0445

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wagner syndrome

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vitreoretinopathy

Benign:1

Jan 12, 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. -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.65

(source)

DANN

Benign

0.38

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over