rs12718598

Variant names:

• chr7-50360747-T-C
• rs12718598
• NM_006060.6:c.161-15786T>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.161-15786T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,196 control chromosomes in the GnomAD database, including 19,238 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 0.50 (19238 hom., cov: 33)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 43 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.161-15786T>C		intron_variant	Intron 3 of 7	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.161-15786T>C		intron_variant	Intron 3 of 7	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75739 AN: 152078 Hom.: 19207 Cov.: 33

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.544

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75833 AN: 152196 Hom.: 19238 Cov.: 33 AF XY: 0.498 AC XY: 37028 AN XY: 74404

African (AFR) AF: 0.515 AC: 21371 AN: 41530

American (AMR) AF: 0.591 AC: 9039 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1917 AN: 3472

East Asian (EAS) AF: 0.406 AC: 2097 AN: 5166

South Asian (SAS) AF: 0.505 AC: 2437 AN: 4826

European-Finnish (FIN) AF: 0.389 AC: 4118 AN: 10594

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33140 AN: 67994

Other (OTH) AF: 0.544 AC: 1151 AN: 2114

Alfa AF: 0.496 Hom.: 79976

Bravo AF: 0.514

Asia WGS AF: 0.483 AC: 1680 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.38
PhyloP100		0.0

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: rs12718598; hg19: chr7-50428445;