rs3093765
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_206937.2(LIG4):c.691C>T(p.Pro231Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
LIG4
NM_206937.2 missense
NM_206937.2 missense
Scores
4
10
4
Clinical Significance
Conservation
PhyloP100: 9.51
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.32838106).
BP6
?
Variant 13-108210578-G-A is Benign according to our data. Variant chr13-108210578-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 834697.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIG4 | NM_206937.2 | c.691C>T | p.Pro231Ser | missense_variant | 3/3 | ENST00000442234.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIG4 | ENST00000442234.6 | c.691C>T | p.Pro231Ser | missense_variant | 3/3 | 1 | NM_206937.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000427 AC: 65AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000124 AC: 31AN: 250152Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135272
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GnomAD4 exome AF: 0.0000383 AC: 56AN: 1460870Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16AN XY: 726750
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GnomAD4 genome ? AF: 0.000427 AC: 65AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 06, 2022 | DNA sequence analysis of the LIG4 gene demonstrated a sequence change, c.691C>T, in exon 2 that results in an amino acid change, p.Pro231Ser. This sequence change does not appear to have been previously described in individuals with LIG4-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.1485% in the African/African American subpopulation (dbSNP rs3093765). The p.Pro231Ser change affects a highly conserved amino acid residue located in a domain of the LIG4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro231Ser substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro231Ser change remains unknown at this time. - |
Multiple myeloma;C1847827:DNA ligase IV deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 05, 2022 | - - |
DNA ligase IV deficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M;M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;.
REVEL
Uncertain
Sift
Uncertain
D;.;D;D;.
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
P;P;P;P;.
Vest4
MVP
MPC
0.092
ClinPred
T
GERP RS
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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