rs1064422
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The ENST00000330377.3(IGLL1):c.425C>T(p.Pro142Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 152,040 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). Synonymous variant affecting the same amino acid position (i.e. P142P) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000330377.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IGLL1 | NM_020070.4 | c.425C>T | p.Pro142Leu | missense_variant | 3/3 | ENST00000330377.3 | NP_064455.1 | |
IGLL1 | NM_001369906.1 | c.428C>T | p.Pro143Leu | missense_variant | 3/3 | NP_001356835.1 | ||
IGLL1 | NM_152855.3 | c.*54C>T | 3_prime_UTR_variant | 2/2 | NP_690594.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IGLL1 | ENST00000330377.3 | c.425C>T | p.Pro142Leu | missense_variant | 3/3 | 1 | NM_020070.4 | ENSP00000329312 | P1 | |
IGLL1 | ENST00000249053.3 | c.*54C>T | 3_prime_UTR_variant | 2/2 | 1 | ENSP00000249053 | ||||
ENST00000458318.2 | n.409G>A | non_coding_transcript_exon_variant | 4/4 | 3 | ||||||
IGLL1 | ENST00000438703.1 | c.428C>T | p.Pro143Leu | missense_variant | 3/3 | 2 | ENSP00000403391 |
Frequencies
GnomAD3 genomes AF: 0.00101 AC: 154AN: 151922Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000299 AC: 75AN: 251082Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135692
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000866 AC: 1264AN: 1459548Hom.: 1 Cov.: 33 AF XY: 0.000855 AC XY: 621AN XY: 726092
GnomAD4 genome AF: 0.00101 AC: 154AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.000996 AC XY: 74AN XY: 74316
ClinVar
Submissions by phenotype
Agammaglobulinemia 2, autosomal recessive Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 05, 1998 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 142 of the IGLL1 protein (p.Pro142Leu). This variant is present in population databases (rs1064422, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with B-cell deficiency and hypogammaglobulinemia (PMID: 9419212). ClinVar contains an entry for this variant (Variation ID: 14825). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
not provided Pathogenic:1Benign:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 01, 2018 | The IGLL1 c.425C>T; p.Pro142Leu variant (rs1064422, ClinVar variant ID 14825) has been found in two patients with agammaglobulinemia and severely reduced B cell levels; one patient was a compound heterozygote, with a premature stop codon on the other chromosome (Minegishi 1998), and the other was a homozygote (Gemayel 2016). Both patients’ IGLL1 genes contained several variants that match the sequence of the highly homologous pseudogene IGLL3P, suggesting the possibility of gene conversion events. Functional studies found that the mutant protein appeared to fold incorrectly and it was not secreted by transfected cells (Minegishi 1998). This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.07% (identified on 85 out of 126,310 chromosomes). The proline at position 142 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Pro142Leu variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the p.Pro142Leu variant is likely to be pathogenic. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | IGLL1: BP4 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
IGLL1-related condition Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2024 | The IGLL1 c.425C>T variant is predicted to result in the amino acid substitution p.Pro142Leu. This variant was reported in two individuals with primary immunodeficiency, one of which was homozygous, and the other of which had a nonsense variant in trans (Giżewska et al. 2020. PubMed ID: 33178177; Minegishi et al. 1998. PubMed ID: 9419212). This variant is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, this variant has been reported in cis along with c.393T>C and c.420T>C, which correspond to reference sequence in the pseudogene and indicates a potential conversion event at this locus (Minegishi et al. 1998. PubMed ID: 9419212). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at