rs1187266733
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_014391.3(ANKRD1):c.849+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,720 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).
Frequency
Consequence
NM_014391.3 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANKRD1 | NM_014391.3 | c.849+1G>C | splice_donor_variant, intron_variant | Intron 8 of 8 | ENST00000371697.4 | NP_055206.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250962Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135638
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1454720Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 723898
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge - |
ANKRD1-related dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2024 | This sequence change affects a donor splice site in intron 8 of the ANKRD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ANKRD1 cause disease. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ANKRD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 477612). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | Feb 13, 2023 | The c.849+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 8 of the ANKRD1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, the evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at