NM_006060.6:c.4G>C
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4BS2
The NM_006060.6(IKZF1):c.4G>C(p.Asp2His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
IKZF1
NM_006060.6 missense
NM_006060.6 missense
Scores
1
8
9
Clinical Significance
Conservation
PhyloP100: 6.88
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the IKZF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.3753 (above the threshold of 3.09). Trascript score misZ: 3.423 (above the threshold of 3.09). GenCC associations: The gene is linked to autoimmune disease, pancytopenia due to IKZF1 mutations.
BP4
Computational evidence support a benign effect (MetaRNN=0.29733285).
BS2
High AC in GnomAdExome4 at 5 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460854Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4AN XY: 726808
GnomAD4 exome
AF:
AC:
5
AN:
1460854
Hom.:
Cov.:
29
AF XY:
AC XY:
4
AN XY:
726808
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
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Gnomad4 OTH exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Apr 23, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;T;.;T;T;T;.;.;.;.;.;T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;D;D;D;.;D;D;D;T;T;T;D;.;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;.;N;D;.;N;N;N;N;N;N;.;N;N;.
REVEL
Benign
Sift
Uncertain
.;.;.;.;D;D;.;D;D;D;D;D;D;.;D;D;.
Sift4G
Uncertain
.;.;.;.;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen
0.61, 1.0, 0.88, 0.73
.;.;P;.;P;D;.;P;.;P;.;.;.;.;P;P;.
Vest4
0.16, 0.33, 0.21, 0.22, 0.17, 0.23, 0.20, 0.22, 0.23, 0.21, 0.22, 0.24
MutPred
Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);Gain of catalytic residue at D4 (P = 0.4795);
MVP
0.26
MPC
1.7
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.