rs374522164
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_014000.3(VCL):c.1352+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014000.3 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.1352+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000211998.10 | |||
VCL | NM_003373.4 | c.1352+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.1352+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251368Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135884
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461708Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727146
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | VCL: PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 468807; Landrum et al., 2016); In silico analysis supports a deleterious effect on splicing - |
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | 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. This sequence change falls in intron 10 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 (rs374522164, gnomAD 0.01%). 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: 468807). 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 may disrupt the consensus splice site. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2020 | The c.1352+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the VCL gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at