rs1060499662
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_206937.2(LIG4):āc.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
NM_206937.2 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 9.24
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 |
---|---|---|---|---|---|---|---|---|
LIG4 | NM_206937.2 | c.2321T>C | p.Leu774Pro | missense_variant | 3/3 | ENST00000442234.6 | NP_996820.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727222
GnomAD4 exome
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1
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1461852
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33
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727222
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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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 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) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;D;D;.
Vest4
MutPred
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
MPC
0.41
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at