rs1060499662

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_206937.2(LIG4):ā€‹c.2321T>Cā€‹(p.Leu774Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.24
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 13-108208948-A-G is Pathogenic according to our data. Variant chr13-108208948-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397529.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-108208948-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LIG4NM_206937.2 linkc.2321T>C p.Leu774Pro missense_variant 3/3 ENST00000442234.6 NP_996820.1 P49917A0A024RE06

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LIG4ENST00000442234.6 linkc.2321T>C p.Leu774Pro missense_variant 3/31 NM_206937.2 ENSP00000402030.1 P49917

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727222
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:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

DNA ligase IV deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaJul 07, 2014This 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) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D;D;D;D;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
.;.;.;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.6
M;M;M;M;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-4.9
D;.;D;D;.
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0030
D;.;D;D;.
Sift4G
Uncertain
0.0080
D;D;D;D;D
Polyphen
1.0
D;D;D;D;.
Vest4
0.97
MutPred
0.73
Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);.;
MVP
0.85
MPC
0.41
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.98
gMVP
0.98

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: rs1060499662; hg19: chr13-108861296; API