7-50327649-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_006060.6(IKZF1):c.52C>A(p.Pro18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
IKZF1
NM_006060.6 missense
NM_006060.6 missense
Scores
2
6
5
Clinical Significance
Conservation
PhyloP100: 5.36
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, IKZF1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IKZF1 | NM_006060.6 | c.52C>A | p.Pro18Thr | missense_variant | 3/8 | ENST00000331340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IKZF1 | ENST00000331340.8 | c.52C>A | p.Pro18Thr | missense_variant | 3/8 | 1 | NM_006060.6 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460098Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4AN XY: 726208
GnomAD4 exome
AF:
AC:
12
AN:
1460098
Hom.:
Cov.:
30
AF XY:
AC XY:
4
AN XY:
726208
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
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the IKZF1 protein (p.Pro18Thr). This variant is present in population databases (rs754640737, gnomAD 0.006%). This missense change has been observed in individual(s) with Acute Lymphoblastic Leukemia (PMID: 29681510). ClinVar contains an entry for this variant (Variation ID: 1972179). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect IKZF1 function (PMID: 29681510). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;.;D;D;D;.;D;D;D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
0.52, 1.0, 0.58
.;.;P;.;P;D;.;P;.;D;.;P;D;.;.
Vest4
0.55, 0.57, 0.64, 0.53, 0.50, 0.68, 0.64, 0.53, 0.68
MutPred
Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);.;
MVP
0.49
MPC
1.7
ClinPred
D
GERP RS
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