rs754882266
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_199242.3(UNC13D):c.1727+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,910 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 Likely pathogenic (★★).
Frequency
Consequence
NM_199242.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UNC13D | NM_199242.3 | c.1727+1G>A | splice_donor_variant | ENST00000207549.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UNC13D | ENST00000207549.9 | c.1727+1G>A | splice_donor_variant | 1 | NM_199242.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249818Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135394
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460910Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 726720
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 3 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The splice site c.1727+1G>A variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1727+1G>A variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.0008% in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. No significant variant in UNC13D gene has been observed in the spouse. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change affects a donor splice site in intron 19 of the UNC13D 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), and loss-of-function variants in UNC13D are known to be pathogenic (PMID: 14622600). This variant is present in population databases (rs754882266, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with UNC13D-related conditions. ClinVar contains an entry for this variant (Variation ID: 533098). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 25, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at