rs772226399

Positions:

• chr13-108209993-CTCTTT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_206937.2(LIG4):​c.1271_1275del​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: LIG4 NM_206937.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• 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]

ACMG classification

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. There are 6 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	Protein	UniProt
LIG4	NM_206937.2	c.1271_1275del	p.Lys424ArgfsTer20	frameshift_variant	3/3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6	c.1271_1275del	p.Lys424ArgfsTer20	frameshift_variant	3/3	1	NM_206937.2	ENSP00000402030	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 250062 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135328

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 316 AN: 1460186 Hom.: 0 AF XY: 0.000202 AC XY: 147 AN XY: 726476

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74514

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000257

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNA ligase IV deficiency Pathogenic:5

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	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. -
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	Labcorp Genetics (formerly Invitae), Labcorp	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2024	Variant summary: LIG4 c.1271_1275delAAAGA (p.Lys424ArgfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 250062 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LIG4 causing LIG4 Syndrome, allowing no conclusion about variant significance. c.1271_1275delAAAGA has been reported in the literature as a biallelic genotype in multiple individuals affected with LIG4 Syndrome (example, Buck_2006, Murray_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete ablation of V(D)J recombination activity in-vitro (example, Buck_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16358361, 24123394). ClinVar contains an entry for this variant (Variation ID: 279838). Based on the evidence outlined above, the variant was classified as pathogenic. -

LIG4-related disorder Pathogenic:3

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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 05, 2024	The LIG4 c.1271_1275del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys424Argfs*20). This variant has been reported in the compound heterozygous state in multiple individuals with clinical features of LIG4 syndrome and segregates with disease in several families (Buck et al. 2006. PubMed ID: 16358361; Walne et al. 2016. PubMed ID: 27612988; Cifaldi et al. 2017. PubMed ID: 27893162; Staines Boone et al. 2018. PubMed ID: 30719430; Bluteau et al. 2018. PubMed ID: 29146883; Duerinckx et al. 2020. PubMed ID: 31696992). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Frameshift variants in LIG4 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772226399; hg19: chr13-108862341;