rs34087182
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PP3_Strong
The NM_000234.3(LIG1):c.1922G>T(p.Arg641Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000583 in 1,613,528 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_000234.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIG1 | NM_000234.3 | c.1922G>T | p.Arg641Leu | missense_variant | 20/28 | ENST00000263274.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIG1 | ENST00000263274.12 | c.1922G>T | p.Arg641Leu | missense_variant | 20/28 | 1 | NM_000234.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251494Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135922
GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461392Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 727040
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
Immunodeficiency 96 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 07, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 25, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects LIG1 function (PMID: 30395541, 32914844, 33444456, 33600799). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with DNA ligase I deficiency (PMID: 30395541). This variant is present in population databases (rs34087182, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 641 of the LIG1 protein (p.Arg641Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at