chr19-48121244-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000234.3(LIG1):c.2311C>T(p.Arg771Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,568 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R771Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000234.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIG1 | NM_000234.3 | c.2311C>T | p.Arg771Trp | missense_variant | 24/28 | ENST00000263274.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIG1 | ENST00000263274.12 | c.2311C>T | p.Arg771Trp | missense_variant | 24/28 | 1 | NM_000234.3 | P4 | |
ENST00000596563.5 | n.161G>A | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 248984Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134854
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461432Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727026
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Immunodeficiency 96 Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 22, 2022 | ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 moderated, PP1 supporting, PP3 supporting - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 771 of the LIG1 protein (p.Arg771Trp). This variant is present in population databases (rs121434561, gnomAD 0.006%). This missense change has been observed in individual(s) with DNA ligase I deficiency (PMID: 1581963, 30395541). ClinVar contains an entry for this variant (Variation ID: 16776). 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. Experimental studies have shown that this missense change affects LIG1 function (PMID: 30395541, 32914844, 33600799). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at