rs4132601

Positions:

• chr7-50402906-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: association criteria provided, single submitter O:1
• 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]

ACMG classification

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: 37341 AN: 152082 Hom.: 4808 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.231 AC: 17709 AN: 76506 Hom.: 2255 Cov.: 0 AF XY: 0.230 AC XY: 8125 AN XY: 35254

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.0869

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.246 AC: 37368 AN: 152200 Hom.: 4813 Cov.: 33 AF XY: 0.249 AC XY: 18509 AN XY: 74420

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.250

Alfa AF: 0.261 Hom.: 12117

Bravo AF: 0.238

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: criteria provided, single submitter

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.7
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4132601; hg19: chr7-50470604;