NM_004385.5:c.4004-1G>T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_004385.5(VCAN):c.4004-1G>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_004385.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VCAN | NM_004385.5 | c.4004-1G>T | splice_acceptor_variant, intron_variant | Intron 7 of 14 | ENST00000265077.8 | NP_004376.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1427716Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 707696
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change affects an acceptor splice site in intron 7 of the VCAN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 13 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Wagner syndrome (PMID: 16043844, 21738396, 23462753, 32623950). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219011). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 8 (PMID: 16043844, 16877430, 21738396). For these reasons, this variant has been classified as Pathogenic. -
Wagner syndrome Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at