7-50402906-T-G

Variant names:

• chr7-50402906-T-G
• rs4132601
• NM_006060.6:c.*2279T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 109 publications found

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]

IKZF1 Gene-Disease associations (from GenCC):

• pancytopenia due to IKZF1 mutations

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• autoimmune disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006060.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	NM_006060.6	MANE Select	c.*2279T>G		3_prime_UTR	Exon 8 of 8	NP_006051.1
	IKZF1	NM_001410879.1		c.*2279T>G		3_prime_UTR	Exon 9 of 9	NP_001397808.1
	IKZF1	NM_001220765.3		c.*2279T>G		3_prime_UTR	Exon 7 of 7	NP_001207694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	ENST00000331340.8	TSL:1 MANE Select	c.*2279T>G		3_prime_UTR	Exon 8 of 8	ENSP00000331614.3
	IKZF1	ENST00000698577.1		n.3074T>G		non_coding_transcript_exon	Exon 2 of 2
	IKZF1	ENST00000642219.2		c.*2279T>G		3_prime_UTR	Exon 8 of 8	ENSP00000496655.2

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

African (AFR) AF: 0.203 AC: 738 AN: 3636

American (AMR) AF: 0.233 AC: 554 AN: 2378

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 1060 AN: 4850

East Asian (EAS) AF: 0.0869 AC: 954 AN: 10982

South Asian (SAS) AF: 0.264 AC: 173 AN: 656

European-Finnish (FIN) AF: 0.321 AC: 18 AN: 56

Middle Eastern (MID) AF: 0.259 AC: 119 AN: 460

European-Non Finnish (NFE) AF: 0.267 AC: 12573 AN: 47106

Other (OTH) AF: 0.238 AC: 1520 AN: 6382

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

African (AFR) AF: 0.196 AC: 8125 AN: 41532

American (AMR) AF: 0.241 AC: 3693 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3472

East Asian (EAS) AF: 0.105 AC: 544 AN: 5182

South Asian (SAS) AF: 0.290 AC: 1396 AN: 4820

European-Finnish (FIN) AF: 0.328 AC: 3469 AN: 10586

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18493 AN: 67994

Other (OTH) AF: 0.250 AC: 528 AN: 2116

Alfa AF: 0.258 Hom.: 24091

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

Laboratorios de Investigación en Biología Molecular e Inmunología, Universidad Autónoma de Nayarit

Significance: association

Review Status: criteria provided, single submitter

Collection Method: research

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.7
DANN	Benign	0.74
PhyloP100		-0.029

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

Other links and lift over

dbSNP: rs4132601; hg19: chr7-50470604;