chr13-108208829-G-A
Variant names:
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
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
LIG4
NM_206937.2 stop_gained
NM_206937.2 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.48
Genes affected
LIG4 (HGNC:6601): (DNA ligase 4) The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.108 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-108208829-G-A is Pathogenic according to our data. Variant chr13-108208829-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108208829-G-A is described in Lovd as [Pathogenic].
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 genomes
AF:
AC:
11
AN:
152068
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251354Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135836
GnomAD3 exomes
AF:
AC:
25
AN:
251354
Hom.:
AF XY:
AC XY:
15
AN XY:
135836
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000153 AC: 224AN: 1461842Hom.: 0 Cov.: 33 AF XY: 0.000171 AC XY: 124AN XY: 727210
GnomAD4 exome
AF:
AC:
224
AN:
1461842
Hom.:
Cov.:
33
AF XY:
AC XY:
124
AN XY:
727210
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74408
GnomAD4 genome
AF:
AC:
11
AN:
152186
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74408
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
0
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
10
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DNA ligase IV deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2025 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2005 | - - |
Pathogenic, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 14, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Jul 07, 2014 | 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) - |
Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 31, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jan 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2025 | LIG4: PM3:Very Strong, PVS1, PM2 - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2016 | - - |
LIG4-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2024 | 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
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
prenatal LIG4 syndrome with aqueductal stenosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics laboratory, Necker Hospital | Dec 28, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at