chr7-50319067-TGCTGATGAGGGTCAAGACATGTCCCAAGTTTCAGGTGAGACCTTATGAGATAGCTGTGTGGGAAGTTCATGAGAAAA-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006060.6(IKZF1):c.10_40+46delGATGAGGGTCAAGACATGTCCCAAGTTTCAGGTGAGACCTTATGAGATAGCTGTGTGGGAAGTTCATGAGAAAAGCT(p.Asp4fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
IKZF1
NM_006060.6 frameshift, splice_donor, splice_region, intron
NM_006060.6 frameshift, splice_donor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.67
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-50319067-TGCTGATGAGGGTCAAGACATGTCCCAAGTTTCAGGTGAGACCTTATGAGATAGCTGTGTGGGAAGTTCATGAGAAAA-T is Pathogenic according to our data. Variant chr7-50319067-TGCTGATGAGGGTCAAGACATGTCCCAAGTTTCAGGTGAGACCTTATGAGATAGCTGTGTGGGAAGTTCATGAGAAAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3779761.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IKZF1 | NM_006060.6 | c.10_40+46delGATGAGGGTCAAGACATGTCCCAAGTTTCAGGTGAGACCTTATGAGATAGCTGTGTGGGAAGTTCATGAGAAAAGCT | p.Asp4fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | Exon 2 of 8 | ENST00000331340.8 | NP_006051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IKZF1 | ENST00000331340.8 | c.7_40+43delGCTGATGAGGGTCAAGACATGTCCCAAGTTTCAGGTGAGACCTTATGAGATAGCTGTGTGGGAAGTTCATGAGAAAA | p.Ala3fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | Exon 2 of 8 | 1 | NM_006060.6 | ENSP00000331614.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pancytopenia due to IKZF1 mutations Pathogenic:1
Jan 04, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.