rs4132601
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_006060.6(IKZF1):c.*2279T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 228,706 control chromosomes in the GnomAD database, including 7,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (★).
Frequency
Genomes: 𝑓 0.25 ( 4813 hom., cov: 33)
Exomes 𝑓: 0.23 ( 2255 hom. )
Consequence
IKZF1
NM_006060.6 3_prime_UTR
NM_006060.6 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0290
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BA1
?
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IKZF1 | NM_006060.6 | c.*2279T>G | 3_prime_UTR_variant | 8/8 | ENST00000331340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IKZF1 | ENST00000331340.8 | c.*2279T>G | 3_prime_UTR_variant | 8/8 | 1 | NM_006060.6 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.246 AC: 37341AN: 152082Hom.: 4808 Cov.: 33
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GnomAD4 exome AF: 0.231 AC: 17709AN: 76506Hom.: 2255 Cov.: 0 AF XY: 0.230 AC XY: 8125AN XY: 35254
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GnomAD4 genome ? AF: 0.246 AC: 37368AN: 152200Hom.: 4813 Cov.: 33 AF XY: 0.249 AC XY: 18509AN XY: 74420
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ClinVar
Significance: association
Submissions summary: Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leukemia, acute lymphocytic, susceptibility to, 2 Other:1
association, criteria provided, single submitter | research | Laboratorios de Investigación en Biología Molecular e Inmunología, Universidad Autónoma de Nayarit | - | In a genome wide association study of 2 case-control series, totaling 907 ALL cases and 2,398 controls, Papaemmanuil et al. (2009) found a significant association between ALL and a SNP at chromosome 7p12.2 in the IKZF1 gene (rs4132601, OR of 1.69, p = 1.20 x 10(-19)). The association was also highly significant when confined to B-cell ALL (OR of 1.73, p = 9.31 x 10(-20)). In vitro studies showed that IKZF1 mRNA expression was significantly associated with genotype in a dose-dependent fashion, with lower expression being associated with the C risk allele. The authors noted that Ikaros proteins are master regulators of lymphocyte development. By genotyping 1,384 cases of precursor B-cell childhood ALL and 1,877 controls from Germany and the United Kingdom, Prasad et al. (2010) found a significant association between IKZF1 SNP rs4132601 and ALL (OR of 1.69, p = 7.51 x 10(-22)). This finding replicated the susceptibility locus for ALL at chromosome 7p12.2 previously reported by Trevino et al. (2009) and Papaemmanuil et al. (2009). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at