NM_004385.5:c.9379+7T>C

Variant names:

• chr5-83545657-T-C
• rs695103
• NM_004385.5:c.9379+7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004385.5(VCAN):​c.9379+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,608,182 control chromosomes in the GnomAD database, including 15,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1115 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13959 hom.)
• Consequence: VCAN NM_004385.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001425
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.685
• Publications: 8 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 (BayesDel_noAF=-0.85).
• BP6: Variant 5-83545657-T-C is Benign according to our data. Variant chr5-83545657-T-C is described in ClinVar as Benign. ClinVar VariationId is 259377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

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.9379+7T>C		splice_region intron	N/A	NP_004376.2
	VCAN	NM_001164097.2		c.6418+7T>C		splice_region intron	N/A	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.4117+7T>C		splice_region intron	N/A	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.9379+7T>C		splice_region intron	N/A	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.6418+7T>C		splice_region intron	N/A	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.4117+7T>C		splice_region intron	N/A	ENSP00000342768.4	P13611-3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16105 AN: 152120 Hom.: 1113 Cov.: 33

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0731

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.139 AC: 34968 AN: 251054 AF XY: 0.152

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.0572

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.126 AC: 183889 AN: 1455944 Hom.: 13959 Cov.: 29 AF XY: 0.133 AC XY: 96256 AN XY: 724804

African (AFR) AF: 0.0523 AC: 1744 AN: 33316

American (AMR) AF: 0.0613 AC: 2739 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3556 AN: 26102

East Asian (EAS) AF: 0.196 AC: 7753 AN: 39654

South Asian (SAS) AF: 0.314 AC: 27052 AN: 86158

European-Finnish (FIN) AF: 0.140 AC: 7476 AN: 53416

Middle Eastern (MID) AF: 0.186 AC: 1070 AN: 5760

European-Non Finnish (NFE) AF: 0.112 AC: 124214 AN: 1106608

Other (OTH) AF: 0.138 AC: 8285 AN: 60220

GnomAD4 genome AF: 0.106 AC: 16116 AN: 152238 Hom.: 1115 Cov.: 33 AF XY: 0.113 AC XY: 8426 AN XY: 74426

African (AFR) AF: 0.0529 AC: 2199 AN: 41560

American (AMR) AF: 0.0732 AC: 1120 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1172 AN: 5176

South Asian (SAS) AF: 0.327 AC: 1576 AN: 4822

European-Finnish (FIN) AF: 0.139 AC: 1472 AN: 10590

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7788 AN: 68002

Other (OTH) AF: 0.114 AC: 242 AN: 2116

Alfa AF: 0.112 Hom.: 2069

Bravo AF: 0.0935

Asia WGS AF: 0.234 AC: 811 AN: 3476

EpiCase AF: 0.120

EpiControl AF: 0.120

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.48
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.11		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: rs695103; hg19: chr5-82841476; COSMIC: COSV54100178;