rs375554612

chr13-108209364-CT-Cchr13-108209364-CT-CTT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_206937.2(LIG4):c.1904del(p.Lys635ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LIG4
NM_206937.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.20

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. There are 12 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-108209364-CT-C is Pathogenic according to our data. Variant chr13-108209364-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 418659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209364-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG4	NM_206937.2 linkuse as main transcript	c.1904del	p.Lys635ArgfsTer10	frameshift_variant	3/3	ENST00000442234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG4	ENST00000442234.6 linkuse as main transcript	c.1904del	p.Lys635ArgfsTer10	frameshift_variant	3/3	1	NM_206937.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251356

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000342

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000755

Hom.:

Bravo

AF:

0.000366

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 19, 2022	PP4, PM1, PM2_supporting, PM3, PVS1_strong -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	The c.1904delA variant in the LIG4 gene has been reported previously in two individuals with LIG4-related disorders who were compound heterozygous for the c.1904delA variant and another loss of function variant (Jspeert et al., 2013; Bluteau et al., 2018). The c.1904delA variant causes a frameshift starting with codon Lysine 635, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Lys635ArgfsX10. This variant is predicted to cause loss of normal protein function through protein truncation of the C-terminal region required for XRCC4 binding and LIG4 stability and activity (Jspeert et al., 2013). The c.1904delA variant is observed in 21/24,016 (0.0874%) alleles from individuals of African background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1904delA as a pathogenic variant. -

DNA ligase IV deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Lys635Argfs10) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 277 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs375554612, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with LIG4 deficiency and bone marrow failure (PMID: 24027040, 28866308, 29146883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 418659). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the LIG4 protein in which other variant(s) (p.Arg814) have been determined to be pathogenic (PMID: 11779494, 16088910, 25239263, 27063650, 27612988). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 20, 2023	PVS1_Moderate, PS3_Moderate, PM1, PM3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2023	Variant summary: LIG4 c.1904delA (p.Lys635ArgfsX10) 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. Truncations downstream of this position have been associated with LIG4 syndrome in HGMD. The variant allele was found at a frequency of 6e-05 in 251356 control chromosomes. c.1904delA has been reported in the literature in individuals affected with LIG4 Syndrome and deficiency (Brunet_2017, IJspeert_2013, Castro_2022) as well as Microcephalic Primordial Dwarfism (Murry_ 2014) and Bone Marrow Failure (Bluteau_2018), both of which can be presentations of LIG4 deficiency. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2021

The c.1904delA (p.K635Rfs*10) alteration, located in exon 2 (coding exon 1) of the LIG4 gene, consists of a deletion of one nucleotide at position 1904, causing a translational frameshift with a predicted alternate stop codon after 10 amino acids. Frameshifts are typically deleterious in nature; however, because LIG4 is a single-exon gene, this alteration is not expected to trigger nonsense-mediated mRNA decay and a(n) altered/truncated protein could still be expressed (Maquat, 2004). This alteration impacts a significant portion of the protein and the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of 0.01% (23/282740) total alleles studied. The highest observed frequency was 0.08% (21/24954) of African alleles. This mutation has been reported in conjunction with a second LIG4 alteration in several individuals with LIG4 syndrome (IJspeert, 2013; Brunet, 2017; Bluteau, 2018). In addition, a downstream truncation alteration, p.R814* c.2440C>T, has been described in individuals with LIG4 syndrome (O'Driscoll, 2001; Ben-Omran, 2005; Walne, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

LIG4-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

The LIG4 c.1904delA variant is predicted to result in a frameshift and premature protein termination (p.Lys635Argfs*10). This variant was reported together with second LIG4 loss-of-function variant in several individuals with LIG4 deficiency (Ijspeert et al. 2013. PubMed ID: 24027040; Brunet et al. 2017. PubMed ID: 28866308; TableS8 and 14; Bluteau et al. 2017. PubMed ID: 29146883). This variant is reported in 0.084% of alleles in individuals of African descent in gnomAD. Frameshift variants in LIG4 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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