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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 3.48

Variant links:

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]

LIG4 links:

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 link	c.2440C>T	p.Arg814*	stop_gained	Exon 3 of 3	ENST00000442234.6	NP_996820.1	P49917A0A024RE06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6 link	c.2440C>T	p.Arg814*	stop_gained	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1		P49917

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251354

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

224

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

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

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 07, 2014

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:4

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LIG4: PM3:Very Strong, PVS1, PM2 -

Oct 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, Oâ€™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. -

Nov 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 06, 2016

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Aug 24, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LIG4-related disorder

Pathogenic:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

prenatal LIG4 syndrome with aqueductal stenosis

Pathogenic:1

Dec 28, 2023

Molecular Genetics laboratory, Necker Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.92

Vest4

0.93

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over