13-108209755-CGAGA-CGAGAGA
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_206937.2(LIG4):c.1512_1513dupTC(p.Arg505LeufsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_206937.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LIG4 | NM_206937.2 | c.1512_1513dupTC | p.Arg505LeufsTer9 | frameshift_variant | Exon 3 of 3 | ENST00000442234.6 | NP_996820.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251388Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135852
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
DNA ligase IV deficiency Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg505Leufs*9) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 407 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs759838407, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LIG4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1338655). This variant disrupts a region of the LIG4 protein in which other variant(s) (p.Arg814*) have been determined to be pathogenic (PMID: 11779494, 16088910, 24123394, 25239263, 27063650, 27612988). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
DNA sequence analysis of the LIG4 gene demonstrated a two base pair duplication in exon 2, c.1512_1513dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon nine amino acids downstream of the duplication, p.Arg505Leufs*9. 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 LIG4 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.0087% in the Latino/Admixed American subpopulation (dbSNP rs759838407). This pathogenic sequence change does not appear to have previously been described in individuals with LIG4-related disorders. Collectively, these evidences indicate that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at