13-108210436-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000442234.6(LIG4):โ€‹c.833G>Aโ€‹(p.Arg278His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,204 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 Pathogenic (โ˜…โ˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R278G) has been classified as Pathogenic.

Frequency

Genomes: ๐‘“ 0.000013 ( 0 hom., cov: 32)
Exomes ๐‘“: 0.000014 ( 0 hom. )

Consequence

LIG4
ENST00000442234.6 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000442234.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-108210436-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2736056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 13-108210436-C-T is Pathogenic according to our data. Variant chr13-108210436-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108210436-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LIG4NM_206937.2 linkuse as main transcriptc.833G>A p.Arg278His missense_variant 3/3 ENST00000442234.6 NP_996820.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LIG4ENST00000442234.6 linkuse as main transcriptc.833G>A p.Arg278His missense_variant 3/31 NM_206937.2 ENSP00000402030 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250408
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135394
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000469
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461002
Hom.:
0
Cov.:
33
AF XY:
0.0000124
AC XY:
9
AN XY:
726748
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DNA ligase IV deficiency Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MรผnchenNov 13, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 278 of the LIG4 protein (p.Arg278His). This variant is present in population databases (rs104894421, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of LIG4 syndrome (PMID: 11779494, 15333585, 27893162, 30719430). 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: 7675). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LIG4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LIG4 function (PMID: 11779494, 15333585, 26608917). This variant disrupts the p.Arg278 amino acid residue in LIG4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26762768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2001- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D;D;D;D;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;.;.;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
M;M;M;M;.
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-5.0
D;.;D;D;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;.;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;D;D;D;.
Vest4
0.96
MutPred
0.87
Gain of catalytic residue at K283 (P = 0.0334);Gain of catalytic residue at K283 (P = 0.0334);Gain of catalytic residue at K283 (P = 0.0334);Gain of catalytic residue at K283 (P = 0.0334);.;
MVP
0.88
MPC
0.36
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.96
gMVP
0.87

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.

Other links and lift over

dbSNP: rs104894421; hg19: chr13-108862784; COSMIC: COSV63597714; API