Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_006060.6(IKZF1):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
IKZF1 (HGNC:13176): (IKAROS family zinc finger 1) This gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The expression of this protein is restricted to the fetal and adult hemo-lymphopoietic system, and it functions as a regulator of lymphocyte differentiation. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. Most isoforms share a common C-terminal domain, which contains two zinc finger motifs that are required for hetero- or homo-dimerization, and for interactions with other proteins. The isoforms, however, differ in the number of N-terminal zinc finger motifs that bind DNA and in nuclear localization signal presence, resulting in members with and without DNA-binding properties. Only a few isoforms contain the requisite three or more N-terminal zinc motifs that confer high affinity binding to a specific core DNA sequence element in the promoters of target genes. The non-DNA-binding isoforms are largely found in the cytoplasm, and are thought to function as dominant-negative factors. Overexpression of some dominant-negative isoforms have been associated with B-cell malignancies, such as acute lymphoblastic leukemia (ALL). [provided by RefSeq, May 2014]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKZF1. . Gene score misZ 3.3753 (greater than the threshold 3.09). Trascript score misZ 3.423 (greater than threshold 3.09). GenCC has associacion of gene with autoimmune disease, pancytopenia due to IKZF1 mutations.
BP4
Computational evidence support a benign effect (MetaRNN=0.07470077).
Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);