7-50382702-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate
The NM_006060.6(IKZF1):c.584A>G(p.His195Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_006060.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pancytopenia due to IKZF1 mutations Pathogenic:1
Mutations in the transcription factor IKAROS (encoded by IKZF1) cause an autosomal dominant antibody deficiency (infections, progressive loss of B cells and immunoglobulins [Ig]). Cytopenia and leukemia may occur. We report a teenager who presents with chronic severe immune thrombocytopenia (ITP) and low serum IgG, IgA, and IgM since age 3. His mother also had low IgG and at age 23 had ITP requiring splenectomy. Neither had frequent infections. Patient and his mother had a novel heterozygous missense mutation in the DNA binding motif zinc finger 3 of IKZF1 (c.584A>G, p.His195Arg). In vitro studies of mutant IKAROS showed loss of characteristic pericentromeric DNA-binding (arrow), consistent with previous findings of other pathogenic mutations (H167R) in IKZF1. IKAROS deficiency may present with ITP in the absence of infections. For ITP patients, we recommend serum Ig screening and evaluation for antibody defects. Identifying the genetic diagnosis in these cases can help anticipate complications in patients and their families. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at