rs104894419

Positions:

chr13-108208829-G-A

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.Arg814Ter) 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:12

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/exons	MANE	Protein	UniProt
LIG4	NM_206937.2 linkuse as main transcript	c.2440C>T	p.Arg814Ter	stop_gained	3/3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6 linkuse as main transcript	c.2440C>T	p.Arg814Ter	stop_gained	3/3	1	NM_206937.2	ENSP00000402030	P1

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DNA ligase IV deficiency

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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 protein 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	- -
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	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

not provided

Pathogenic:3

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	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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -

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: 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

MutationTaster

Benign

1.0

A;A;A

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