7-50393986-G-A

Variant names:

• chr7-50393986-G-A
• rs10248903
• NM_006060.6:c.850+2123G>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.850+2123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 232,046 control chromosomes in the GnomAD database, including 58,652 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 0.71 (38602 hom., cov: 32)
  • Exomes 𝑓: 0.68 (20050 hom.)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 5 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=-0.9).
• 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.850+2123G>A		intron_variant	Intron 7 of 7	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.850+2123G>A		intron_variant	Intron 7 of 7	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107255 AN: 151904 Hom.: 38567 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.757

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.725

GnomAD4 exome AF: 0.684 AC: 54770 AN: 80022 Hom.: 20050 Cov.: 0 AF XY: 0.687 AC XY: 25277 AN XY: 36792

African (AFR) AF: 0.683 AC: 2623 AN: 3840

American (AMR) AF: 0.623 AC: 1535 AN: 2462

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 3872 AN: 5066

East Asian (EAS) AF: 0.255 AC: 2872 AN: 11280

South Asian (SAS) AF: 0.639 AC: 442 AN: 692

European-Finnish (FIN) AF: 0.641 AC: 41 AN: 64

Middle Eastern (MID) AF: 0.712 AC: 346 AN: 486

European-Non Finnish (NFE) AF: 0.773 AC: 38225 AN: 49442

Other (OTH) AF: 0.720 AC: 4814 AN: 6690

GnomAD4 genome AF: 0.706 AC: 107335 AN: 152024 Hom.: 38602 Cov.: 32 AF XY: 0.701 AC XY: 52069 AN XY: 74298

African (AFR) AF: 0.664 AC: 27502 AN: 41438

American (AMR) AF: 0.637 AC: 9735 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 2627 AN: 3472

East Asian (EAS) AF: 0.278 AC: 1434 AN: 5166

South Asian (SAS) AF: 0.658 AC: 3170 AN: 4816

European-Finnish (FIN) AF: 0.748 AC: 7897 AN: 10564

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52543 AN: 67978

Other (OTH) AF: 0.719 AC: 1513 AN: 2104

Alfa AF: 0.749 Hom.: 22617

Bravo AF: 0.696

Asia WGS AF: 0.514 AC: 1790 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.55
DANN	Benign	0.37
PhyloP100		-2.0

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: rs10248903; hg19: chr7-50461684;