22-23573314-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020070.4(IGLL1):c.594C>A(p.His198Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,110 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 (★★).
Frequency
Consequence
NM_020070.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IGLL1 | NM_020070.4 | c.594C>A | p.His198Gln | missense_variant | Exon 3 of 3 | ENST00000330377.3 | NP_064455.1 | |
IGLL1 | NM_001369906.1 | c.597C>A | p.His199Gln | missense_variant | Exon 3 of 3 | NP_001356835.1 | ||
IGLL1 | NM_152855.3 | c.*223C>A | 3_prime_UTR_variant | Exon 2 of 2 | NP_690594.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IGLL1 | ENST00000330377.3 | c.594C>A | p.His198Gln | missense_variant | Exon 3 of 3 | 1 | NM_020070.4 | ENSP00000329312.2 | ||
IGLL1 | ENST00000249053 | c.*223C>A | 3_prime_UTR_variant | Exon 2 of 2 | 1 | ENSP00000249053.3 | ||||
ENSG00000224277 | ENST00000458318.2 | n.391-151G>T | intron_variant | Intron 3 of 3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 151446Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251250Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135820
GnomAD4 exome AF: 0.000192 AC: 281AN: 1461544Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 139AN XY: 727062
GnomAD4 genome AF: 0.000158 AC: 24AN: 151566Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74116
ClinVar
Submissions by phenotype
Agammaglobulinemia 2, autosomal recessive Uncertain:2
This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 198 of the IGLL1 protein (p.His198Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with IGLL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1021143). 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. -
The homozygous p.His198Gln missense variant identified in IGLL1 has not been reported in affected individuals in the literature. The variant has 0.0001262 allele frequency in the genomAD(v3) database (18 out of 142,618 heterozygous alleles, no homozygote) indicating it is a rare allele in the populations represented in this database. The variant affects an evolutionary conserved Histidine residue at position 198 and is predicted deleterious by multiple in silico prediction tools. Based on the current evidence, the p.His198Gln variant in the IGLL1gene is assessed as a variant of uncertain significance. -
not provided Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at