5-83483587-A-T

Variant names:

• chr5-83483587-A-T
• rs768072971
• ENST00000512590:c.-76A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The ENST00000512590(VCAN):​c.-76A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VCAN ENST00000512590 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.1288
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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]

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=0.26879102).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000205 (3/1460796) while in subpopulation EAS AF= 0.0000758 (3/39580). AF 95% confidence interval is 0.0000201. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.69A>T	p.Lys23Asn	missense_variant, splice_region_variant	Exon 2 of 15	ENST00000265077.8	NP_004376.2
VCAN	NM_001164097.2	c.69A>T	p.Lys23Asn	missense_variant, splice_region_variant	Exon 2 of 14		NP_001157569.1
VCAN	NM_001164098.2	c.69A>T	p.Lys23Asn	missense_variant, splice_region_variant	Exon 2 of 14		NP_001157570.1
VCAN	NM_001126336.3	c.69A>T	p.Lys23Asn	missense_variant, splice_region_variant	Exon 2 of 13		NP_001119808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.69A>T	p.Lys23Asn	missense_variant, splice_region_variant	Exon 2 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251144 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with VCAN-related conditions. This variant is present in population databases (rs768072971, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 23 of the VCAN protein (p.Lys23Asn). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.4	L;L;L;.;.;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D;T;T
Sift4G	Benign	0.24	T;D;T;D;T;T
Polyphen		0.74	P;P;B;.;B;B
Vest4		0.30
MutPred		0.58		Loss of methylation at K23 (P = 0.0206);Loss of methylation at K23 (P = 0.0206);Loss of methylation at K23 (P = 0.0206);Loss of methylation at K23 (P = 0.0206);Loss of methylation at K23 (P = 0.0206);Loss of methylation at K23 (P = 0.0206);
MVP		0.81
MPC		0.18
ClinPred		0.62	D
GERP RS		4.2
Varity_R		0.14
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.43
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

LitVar

Other links and lift over

dbSNP: rs768072971; hg19: chr5-82779406;