rs767694507
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_014000.3(VCL):c.783+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014000.3 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.783+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000211998.10 | |||
VCL | NM_003373.4 | c.783+5G>A | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.783+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251106Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135788
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461818Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727208
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2022 | This sequence change falls in intron 6 of the VCL gene. It does not directly change the encoded amino acid sequence of the VCL protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs767694507, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with VCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 567280). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2023 | The c.783+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 6 in the VCL gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at