rs6954833

Variant names:

• chr7-50390748-G-A
• rs6954833
• NM_006060.6:c.716-981G>A

Variant summary

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

The NM_006060.6(IKZF1):​c.716-981G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 152,178 control chromosomes in the GnomAD database, including 43,502 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 0.75 (43502 hom., cov: 33)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183
• Publications: 11 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

ENSG00000285165 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.807 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.716-981G>A		intron	N/A	NP_006051.1
	IKZF1	NM_001410879.1		c.776-981G>A		intron	N/A	NP_001397808.1
	IKZF1	NM_001220765.3		c.590-981G>A		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.716-981G>A		intron	N/A	ENSP00000331614.3
	IKZF1	ENST00000359197.9	TSL:1	c.590-981G>A		intron	N/A	ENSP00000352123.5
	IKZF1	ENST00000439701.2	TSL:1	c.590-981G>A		intron	N/A	ENSP00000413025.1

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114621 AN: 152058 Hom.: 43448 Cov.: 33

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.777

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

GnomAD4 genome AF: 0.754 AC: 114734 AN: 152178 Hom.: 43502 Cov.: 33 AF XY: 0.753 AC XY: 56016 AN XY: 74380

African (AFR) AF: 0.737 AC: 30596 AN: 41506

American (AMR) AF: 0.819 AC: 12516 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2686 AN: 3470

East Asian (EAS) AF: 0.468 AC: 2424 AN: 5178

South Asian (SAS) AF: 0.690 AC: 3329 AN: 4824

European-Finnish (FIN) AF: 0.747 AC: 7910 AN: 10590

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.775 AC: 52719 AN: 68006

Other (OTH) AF: 0.775 AC: 1635 AN: 2110

Alfa AF: 0.769 Hom.: 32907

Bravo AF: 0.760

Asia WGS AF: 0.623 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.81
DANN	Benign	0.56
PhyloP100		-0.18

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: rs6954833; hg19: chr7-50458446;