rs34050047

Variant names:

• chr5-83538579-C-A
• rs34050047
• NM_004385.5:c.5576C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-83538579-C-A
• chr5-83538579-C-G
• chr5-83538579-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004385.5(VCAN):​c.5576C>A​(p.Ala1859Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,613,974 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1859V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (49 hom.)
• Consequence: VCAN NM_004385.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.64
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021563172).
• BP6: Variant 5-83538579-C-A is Benign according to our data. Variant chr5-83538579-C-A is described in ClinVar as Benign. ClinVar VariationId is 259368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1861/152188) while in subpopulation AFR AF = 0.0426 (1767/41510). AF 95% confidence interval is 0.0409. There are 39 homozygotes in GnomAd4. There are 882 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1861 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.5576C>A	p.Ala1859Glu	missense	Exon 8 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.2615C>A	p.Ala872Glu	missense	Exon 7 of 14	NP_001157569.1
	VCAN	NM_001164098.2		c.4004-6958C>A		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.5576C>A	p.Ala1859Glu	missense	Exon 8 of 15	ENSP00000265077.3
	VCAN	ENST00000343200.9	TSL:1	c.2615C>A	p.Ala872Glu	missense	Exon 7 of 14	ENSP00000340062.5
	VCAN	ENST00000513960.5	TSL:1	c.2615C>A	p.Ala872Glu	missense	Exon 7 of 7	ENSP00000426251.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1845 AN: 152070 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.00299 AC: 750 AN: 250694 AF XY: 0.00225

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00130 AC: 1899 AN: 1461786 Hom.: 49 Cov.: 80 AF XY: 0.00116 AC XY: 844 AN XY: 727210

African (AFR) AF: 0.0460 AC: 1540 AN: 33474

American (AMR) AF: 0.00197 AC: 88 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111938

Other (OTH) AF: 0.00308 AC: 186 AN: 60384

GnomAD4 genome AF: 0.0122 AC: 1861 AN: 152188 Hom.: 39 Cov.: 32 AF XY: 0.0119 AC XY: 882 AN XY: 74406

African (AFR) AF: 0.0426 AC: 1767 AN: 41510

American (AMR) AF: 0.00504 AC: 77 AN: 15286

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

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.00484 Hom.: 27

Bravo AF: 0.0148

ESP6500AA AF: 0.0388 AC: 171

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00355 AC: 431

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.9
DANN	Benign	0.67
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		1.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.092
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.065
MVP		0.10
MPC		0.091
ClinPred		0.0020	T
GERP RS		0.77
Varity_R		0.044
gMVP		0.10
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: rs34050047; hg19: chr5-82834398;