rs772226399
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206937.2(LIG4):βc.1271_1275delβ(p.Lys424ArgfsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,612,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.00025 ( 0 hom., cov: 32)
Exomes π: 0.00022 ( 0 hom. )
Consequence
LIG4
NM_206937.2 frameshift
NM_206937.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.81
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 18 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. There are 35 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-108209993-CTCTTT-C is Pathogenic according to our data. Variant chr13-108209993-CTCTTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 279838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209993-CTCTTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIG4 | NM_206937.2 | c.1271_1275del | p.Lys424ArgfsTer20 | frameshift_variant | 3/3 | ENST00000442234.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIG4 | ENST00000442234.6 | c.1271_1275del | p.Lys424ArgfsTer20 | frameshift_variant | 3/3 | 1 | NM_206937.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000250 AC: 38AN: 152220Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
38
AN:
152220
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: 0.000156 AC: 39AN: 250062Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135328
GnomAD3 exomes
AF:
AC:
39
AN:
250062
Hom.:
AF XY:
AC XY:
21
AN XY:
135328
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: 0.000216 AC: 316AN: 1460186Hom.: 0 AF XY: 0.000202 AC XY: 147AN XY: 726476
GnomAD4 exome
AF:
AC:
316
AN:
1460186
Hom.:
AF XY:
AC XY:
147
AN XY:
726476
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: 0.000249 AC: 38AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74514
GnomAD4 genome
?
AF:
AC:
38
AN:
152338
Hom.:
Cov.:
32
AF XY:
AC XY:
16
AN XY:
74514
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:
Asia WGS
AF:
AC:
1
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DNA ligase IV deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 17, 2021 | ACMG classification criteria: PVS1 very strong, PS4 moderate, PM3 very strong, PP1 moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Lys424Argfs*20) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 488 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs772226399, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of LIG4 syndrome (PMID: 16358631, 24123394, 27612988, 27893162, 29146883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as K424fs. ClinVar contains an entry for this variant (Variation ID: 279838). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | May 18, 2018 | LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of LIG4 syndrome (most commonly immunodeficiency and failure to thrive), segregating with disease in at least 3 affected family members (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162, Jiang 2016 PMID:26762768, Walne 2016 PMID:27612988). This variant is present in 27/126568 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772226399). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:279838). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, functional studies suggest that this variant may result in increased sensitivity to radiation (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162). This variant represents a deletion of 5 nucelotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic. - |
LIG4-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The LIG4 c.1271_1275delAAAGA (p.Lys424ArgfsTer20) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Lys424ArgfsTer20 variant has been reported in five studies in which it is found in a compound heterozygous state in 14 individuals with LIG4-related disorders from 11 unrelated families (Buck et al. 2006; Enders et al. 2006; Murray et al. 2014; Jiang et al. 2016; Walne et al. 2016). In all cases, the p.Lys424ArgfsTer20 variant was inherited from a healthy heterozygous parent. Two of these patients were diagnosed with dyskeratosis congenita; the authors state that clinical symptoms in these patients had substantial overlap with LIG4 syndrome (Walne et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. Buck et al. (2006) showed that Lig4 protein expression in fibroblasts from one patient was significantly reduced compared to wild type, and a cell survival assay in fibroblasts from a second patient showed increased sensitivity to ionizing radiation. Based on the evidence and potential impact of frameshift variants, the p.Lys424ArgfsTer20 is classified as pathogenic for LIG4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2023 | Published functional studies demonstrate a damaging effect on Lig4 protein levels (Buck et al., 2006); Frameshift variant predicted to result in protein truncation, as the last 488 amino acids are replaced with 19 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 27893162, 26762768, 16358361, 27612988, 16585603, 24123394, 30719430, 31696992, 31980526, 34426522, 29146883, 32471509, 31589614, 35595529, 34313030, 34630384, 35665479, 37437665, 36221079) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | LIG4: PVS1, PM3, PM2:Supporting - |
Multiple myeloma;C1847827:DNA ligase IV deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of LIG4 syndrome (most commonly immunodeficiency and failure to thrive), segregating with disease in at least 3 affected family members (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162, Jiang 2016 PMID:26762768, Walne 2016 PMID:27612988). This variant is present in 27/126568 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772226399). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:279838). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, functional studies suggest that this variant may result in increased sensitivity to radiation (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162). This variant represents a deletion of 5 nucelotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at