rs764196809
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_199242.3(UNC13D):c.2346_2349del(p.Arg782SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
UNC13D
NM_199242.3 frameshift
NM_199242.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.57
Genes affected
UNC13D (HGNC:23147): (unc-13 homolog D) This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-75834092-ACTCC-A is Pathogenic according to our data. Variant chr17-75834092-ACTCC-A is described in ClinVar as [Pathogenic]. Clinvar id is 420155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UNC13D | NM_199242.3 | c.2346_2349del | p.Arg782SerfsTer12 | frameshift_variant | 24/32 | ENST00000207549.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UNC13D | ENST00000207549.9 | c.2346_2349del | p.Arg782SerfsTer12 | frameshift_variant | 24/32 | 1 | NM_199242.3 | P1 | |
UNC13D | ENST00000412096.6 | c.2346_2349del | p.Arg782SerfsTer12 | frameshift_variant | 24/33 | 2 | |||
UNC13D | ENST00000699510.1 | c.1212_1215del | p.Arg404SerfsTer12 | frameshift_variant | 12/20 | ||||
UNC13D | ENST00000591563.5 | n.2616_2619del | non_coding_transcript_exon_variant | 22/23 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000658 AC: 10AN: 151990Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 250908Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135734
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GnomAD4 exome AF: 0.000158 AC: 231AN: 1461458Hom.: 0 AF XY: 0.000147 AC XY: 107AN XY: 727036
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 3 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Aug 06, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Arg782Serfs*12) 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 (rs764196809, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with familial hemophagocytic lymphohistiocytosis (PMID: 16278825, 18492689, 19484379, 20823128, 21248318, 26342526). ClinVar contains an entry for this variant (Variation ID: 420155). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 06, 2021 | DNA sequence analysis of the UNC13D gene demonstrated a four base pair deletion in exon 24, c.2346_2349del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 12 amino acids downstream of the change, p.Arg782Serfs*12. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated UNC13D protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.02%in the non-Finnish European subpopulation (dbSNP rs764196809). This pathogenic sequence change has previously been described in an individuals with UNC13D-related hemophagocytic lymphohistiocytosis (PMID: 16278825, 32542393, 20823128, 17993578, 30295794). Collectively these evidences suggest that, the c.2346_2349del change is likely pathogenic, however functional studies have not been performed to prove this conclusively. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32542393, 30760465, 26342526, 28973083, 16825436, 16278825, 17993578, 20823128) - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 06, 2017 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at