rs61733395

Variant names:

• chr5-83537425-T-C
• rs61733395
• NM_004385.5:c.4422T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004385.5(VCAN):​c.4422T>C​(p.Thr1474Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,918 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (12 hom.)
• Consequence: VCAN NM_004385.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -6.53
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 5-83537425-T-C is Benign according to our data. Variant chr5-83537425-T-C is described in ClinVar as Benign. ClinVar VariationId is 259365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00907 (1380/152214) while in subpopulation AFR AF = 0.0316 (1311/41534). AF 95% confidence interval is 0.0301. There are 28 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1380 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.4422T>C	p.Thr1474Thr	synonymous	Exon 8 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.1461T>C	p.Thr487Thr	synonymous	Exon 7 of 14	NP_001157569.1
	VCAN	NM_001164098.2		c.4004-8112T>C		intron	N/A	NP_001157570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.4422T>C	p.Thr1474Thr	synonymous	Exon 8 of 15	ENSP00000265077.3
	VCAN	ENST00000343200.9	TSL:1	c.1461T>C	p.Thr487Thr	synonymous	Exon 7 of 14	ENSP00000340062.5
	VCAN	ENST00000513960.5	TSL:1	c.1461T>C	p.Thr487Thr	synonymous	Exon 7 of 7	ENSP00000426251.1

Frequencies

GnomAD3 genomes AF: 0.00901 AC: 1370 AN: 152096 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

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: 0.0000588

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00232 AC: 582 AN: 250542 AF XY: 0.00165

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000974 AC: 1423 AN: 1461704 Hom.: 12 Cov.: 70 AF XY: 0.000825 AC XY: 600 AN XY: 727158

African (AFR) AF: 0.0322 AC: 1077 AN: 33466

American (AMR) AF: 0.00239 AC: 107 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111924

Other (OTH) AF: 0.00267 AC: 161 AN: 60388

GnomAD4 genome AF: 0.00907 AC: 1380 AN: 152214 Hom.: 28 Cov.: 32 AF XY: 0.00915 AC XY: 681 AN XY: 74416

African (AFR) AF: 0.0316 AC: 1311 AN: 41534

American (AMR) AF: 0.00347 AC: 53 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00331 Hom.: 10

Bravo AF: 0.0107

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.68
DANN	Benign	0.48
PhyloP100		-6.5
Mutation Taster		=98/2	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: rs61733395; hg19: chr5-82833244;