NM_206937.2:c.2440C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_206937.2(LIG4):c.2440C>T(p.Arg814*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,028 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 (★★).
Frequency
Consequence
NM_206937.2 stop_gained
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.2440C>T | p.Arg814* | stop_gained | Exon 3 of 3 | ENST00000442234.6 | NP_996820.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251354Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135836
GnomAD4 exome AF: 0.000153 AC: 224AN: 1461842Hom.: 0 Cov.: 33 AF XY: 0.000171 AC XY: 124AN XY: 727210
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74408
ClinVar
Submissions by phenotype
DNA ligase IV deficiency Pathogenic:5
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This sequence change creates a premature translational stop signal (p.Arg814*) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs104894419, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Ligase IV syndrome (PMID: 11779494, 16088910, 24123394, 25239263, 27063650, 27612988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7673). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LIG4 function (PMID: 15333585, 24892279, 27063650). For these reasons, this variant has been classified as Pathogenic. -
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This heterozygous variant in the LIG4 gene (autosomal recessive transmission) was identified in a twin pair (one male and one female patient) with extreme growth delay, who also harbours another variant in the LIG4 gene (compound heterozygosity) -
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not provided Pathogenic:4
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LIG4: PM3:Very Strong, PVS1, PM2 -
The LIG4 c.2440C>T; p.Arg814Ter variant (rs104894419) is reported in the literature in multiple homozygous and compound heterozygous individuals affected with LIG4 syndrome (Ben-Omran 2005, Murray 2014, O’Driscoll 2001). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (24/129,080 alleles) in the Genome Aggregation Database (v2.1.1). This variant results in a premature termination codon in the last exon of the LIG4 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated LIG4 protein. Functional assays demonstrate the variant protein has reduced interaction with binding partners and significantly reduced enzymatic activity (Girard 2004). Based on available information, this variant is considered to be pathogenic. References: Ben-Omran TI et al. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A. 2005 Sep 1;137A(3):283-7. PMID: 16088910. Girard PM et al. Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Hum Mol Genet. 2004 Oct 15;13(20):2369-76. PMID: 15333585. Murray JE et al. Extreme growth failure is a common presentation of ligase IV deficiency. Hum Mutat. 2014 Jan;35(1):76-85. PMID: 24123394. O'Driscoll M et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001 Dec;8(6):1175-85. PMID: 11779494. -
Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate less than 1% residual activity and significantly impaired interaction with XRCC4 and NAD+ (Girard et al., 2004; Chen et al., 2018); This variant is associated with the following publications: (PMID: 11779494, 27855655, 26608917, 24892279, 27537055, 27353043, 27612988, 25239263, 29146883, 30719430, 30496552, 31130284, 31980526, 33739554, 31589614, 24123394, 16088910, 15333585, 27063650, 23372718) -
Inborn genetic diseases Pathogenic:1
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LIG4-related disorder Pathogenic:1
The LIG4 c.2440C>T variant is predicted to result in premature protein termination (p.Arg814*). This variant has been reported in the compound heterozygous state in individuals with ligase IV syndrome (O'Driscoll et al. 2001. PubMed ID: 11779494; Felgentreff et al. 2016. PubMed ID: 27063650). This variant has also been reported in the compound heterozygous state in individuals with atypical Seckel syndrome, Dubowitz syndrome, dyskeratosis congenita, and microcephalic primordial dwarfism (Murray et al. 2014. PubMed ID: 24123394; Zhang et al. 2015. PubMed ID: 25239263; Walne et al. 2016. PubMed ID: 27612988). Functional studies have shown that this variant leads to increased cellular radiosensitivity, diminished cell survival, decreased binding to XRCC4, increased DNA damage, and delayed kinetics of DNA repair (Girard et al. 2004. PubMed ID: 15333585; Stewart et al. 2014. PubMed ID: 24892279; Felgentreff et al. 2016. PubMed ID: 27063650). This variant is reported in 0.019% of alleles in individuals of European (non-Finnish) descent in gnomAD. Nonsense variants in LIG4 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Multiple myeloma;C1847827:DNA ligase IV deficiency Pathogenic:1
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prenatal LIG4 syndrome with aqueductal stenosis Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at