7-50402283-T-C

Variant names:

• chr7-50402283-T-C
• rs11980379
• NM_006060.6:c.*1656T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006060.6(IKZF1):​c.*1656T>C 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 230,314 control chromosomes in the GnomAD database, including 7,130 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4810 hom., cov: 33)
  • Exomes 𝑓: 0.23 (2320 hom.)
• Consequence: IKZF1 NM_006060.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.181
• Publications: 38 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=-0.87).
• 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.*1656T>C		3_prime_UTR	Exon 8 of 8	NP_006051.1
	IKZF1	NM_001410879.1		c.*1656T>C		3_prime_UTR	Exon 9 of 9	NP_001397808.1
	IKZF1	NM_001220765.3		c.*1656T>C		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.*1656T>C		3_prime_UTR	Exon 8 of 8	ENSP00000331614.3
	IKZF1	ENST00000359197.9	TSL:1	c.*1656T>C		3_prime_UTR	Exon 7 of 7	ENSP00000352123.5
	IKZF1	ENST00000439701.2	TSL:1	c.*1656T>C		3_prime_UTR	Exon 7 of 7	ENSP00000413025.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37329 AN: 152076 Hom.: 4805 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.293

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: 0.233 AC: 18195 AN: 78120 Hom.: 2320 Cov.: 0 AF XY: 0.232 AC XY: 8365 AN XY: 36006

African (AFR) AF: 0.206 AC: 767 AN: 3724

American (AMR) AF: 0.234 AC: 563 AN: 2402

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 1099 AN: 4958

East Asian (EAS) AF: 0.0883 AC: 983 AN: 11138

South Asian (SAS) AF: 0.275 AC: 190 AN: 692

European-Finnish (FIN) AF: 0.339 AC: 19 AN: 56

Middle Eastern (MID) AF: 0.264 AC: 124 AN: 470

European-Non Finnish (NFE) AF: 0.268 AC: 12899 AN: 48144

Other (OTH) AF: 0.237 AC: 1551 AN: 6536

GnomAD4 genome AF: 0.245 AC: 37356 AN: 152194 Hom.: 4810 Cov.: 33 AF XY: 0.249 AC XY: 18499 AN XY: 74408

African (AFR) AF: 0.196 AC: 8120 AN: 41522

American (AMR) AF: 0.241 AC: 3692 AN: 15296

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

East Asian (EAS) AF: 0.105 AC: 545 AN: 5190

South Asian (SAS) AF: 0.289 AC: 1397 AN: 4826

European-Finnish (FIN) AF: 0.328 AC: 3477 AN: 10592

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

European-Non Finnish (NFE) AF: 0.272 AC: 18480 AN: 67986

Other (OTH) AF: 0.249 AC: 525 AN: 2108

Alfa AF: 0.258 Hom.: 22864

Bravo AF: 0.238

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.1
DANN	Benign	0.64
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs11980379; hg19: chr7-50469981;