7-50306538-C-T

Variant names:

• chr7-50306538-C-T
• rs7781977
• NM_006060.6:c.-15+1616C>T

Variant summary

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

The ENST00000331340.8(IKZF1):​c.-15+1616C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 151,992 control chromosomes in the GnomAD database, including 7,953 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 0.32 (7953 hom., cov: 32)
• Consequence: IKZF1 ENST00000331340.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 17 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000331340.8. 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.-15+1616C>T		intron	N/A	NP_006051.1
	IKZF1	NM_001410879.1		c.-15+2008C>T		intron	N/A	NP_001397808.1
	IKZF1	NM_001220765.3		c.-15+1616C>T		intron	N/A	NP_001207694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	ENST00000331340.8	TSL:1 MANE Select	c.-15+1616C>T		intron	N/A	ENSP00000331614.3
	IKZF1	ENST00000359197.9	TSL:1	c.-15+1616C>T		intron	N/A	ENSP00000352123.5
	IKZF1	ENST00000413698.5	TSL:1	c.-15+1616C>T		intron	N/A	ENSP00000388478.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47941 AN: 151874 Hom.: 7940 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.310

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

GnomAD4 genome AF: 0.316 AC: 47999 AN: 151992 Hom.: 7953 Cov.: 32 AF XY: 0.318 AC XY: 23635 AN XY: 74288

African (AFR) AF: 0.295 AC: 12228 AN: 41420

American (AMR) AF: 0.433 AC: 6611 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 821 AN: 3468

East Asian (EAS) AF: 0.492 AC: 2540 AN: 5164

South Asian (SAS) AF: 0.367 AC: 1770 AN: 4826

European-Finnish (FIN) AF: 0.272 AC: 2866 AN: 10556

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.297 AC: 20158 AN: 67964

Other (OTH) AF: 0.314 AC: 663 AN: 2112

Alfa AF: 0.306 Hom.: 22873

Bravo AF: 0.324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.61
DANN	Benign	0.46
PhyloP100		-2.1

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: rs7781977; hg19: chr7-50346134;