rs121434352
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_199242.3(UNC13D):c.766C>T(p.Arg256Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_199242.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UNC13D | NM_199242.3 | c.766C>T | p.Arg256Ter | stop_gained | 10/32 | ENST00000207549.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UNC13D | ENST00000207549.9 | c.766C>T | p.Arg256Ter | stop_gained | 10/32 | 1 | NM_199242.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249946Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135476
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461438Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727012
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 3 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg256*) in the UNC13D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UNC13D are known to be pathogenic (PMID: 14622600). This variant is present in population databases (rs121434352, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 14622600, 21152410, 21674762, 24470399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2000). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 29, 2018 | The UNC13D c.766C>T (p.Arg256Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The c.766C>T (p.Arg256Ter) variant has been reported in five studies and is found in seven individuals with familial hemophagocytic lymphohistiocytosis in a compound heterozygous state (Feldmann et al. 2003; Zur Stadt et al. 2006; Nagai et al. 2010; Zhizhuo et al. 2012; Qian et al. 2014). The variant was absent from 276 control subjects and is present at a frequency of 0.000046 in the European (non-Finnish) population of the Exome Aggregation Consortium. Western blotting experiments showed that the p.Arg256Ter variant resulted in an absence of protein expression (Nagai et al. 2010). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Arg256Ter variant is considered to be pathogenic for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 14, 2003 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2019 | The R256X nonsense variant has been reported previously in trans with another pathogenic variant in association with familial hemophagocytic lymphohistiocytosis (Feldmann et al., 2003). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret this variant as pathogenic. - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at