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
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, IKZF1
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
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);