chr7-50384854-G-A

Variant names:

• chr7-50384854-G-A
• rs10230385
• NM_006060.6:c.589+2147G>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.589+2147G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 152,160 control chromosomes in the GnomAD database, including 37,462 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 0.69 (37462 hom., cov: 33)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.586
• Publications: 9 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.589+2147G>A		intron_variant	Intron 5 of 7	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.589+2147G>A		intron_variant	Intron 5 of 7	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105588 AN: 152040 Hom.: 37434 Cov.: 33

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.716

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

GnomAD4 genome AF: 0.694 AC: 105659 AN: 152160 Hom.: 37462 Cov.: 33 AF XY: 0.690 AC XY: 51335 AN XY: 74414

African (AFR) AF: 0.625 AC: 25939 AN: 41504

American (AMR) AF: 0.629 AC: 9614 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2644 AN: 3470

East Asian (EAS) AF: 0.278 AC: 1440 AN: 5184

South Asian (SAS) AF: 0.656 AC: 3169 AN: 4830

European-Finnish (FIN) AF: 0.747 AC: 7913 AN: 10588

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52526 AN: 67976

Other (OTH) AF: 0.711 AC: 1502 AN: 2114

Alfa AF: 0.740 Hom.: 162144

Bravo AF: 0.682

Asia WGS AF: 0.510 AC: 1779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.19
DANN	Benign	0.59
PhyloP100		-0.59

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: rs10230385; hg19: chr7-50452552;