chr5-83483549-A-T

Position:

• chr5-83483549-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000512590(VCAN):​c.-114A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN ENST00000512590 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17953104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCAN	NM_004385.5	c.31A>T	p.Met11Leu	missense_variant	2/15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.31A>T	p.Met11Leu	missense_variant	2/14		NP_001157569.1
VCAN	NM_001164098.2	c.31A>T	p.Met11Leu	missense_variant	2/14		NP_001157570.1
VCAN	NM_001126336.3	c.31A>T	p.Met11Leu	missense_variant	2/13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.31A>T	p.Met11Leu	missense_variant	2/15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the VCAN protein (p.Met11Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VCAN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0038	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.15	T;.;.;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T;T;T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.2	L;L;L;.;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.033	D;D;D;D;T;T
Sift4G	Benign	0.32	T;T;T;D;T;T
Polyphen		0.0020	B;B;B;.;B;B
Vest4		0.33
MutPred		0.38		Gain of ubiquitination at K6 (P = 0.0831);Gain of ubiquitination at K6 (P = 0.0831);Gain of ubiquitination at K6 (P = 0.0831);Gain of ubiquitination at K6 (P = 0.0831);Gain of ubiquitination at K6 (P = 0.0831);Gain of ubiquitination at K6 (P = 0.0831);
MVP		0.50
MPC		0.075
ClinPred		0.29	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-82779368;