chr7-50319087-T-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_006060.6(IKZF1):c.26T>C(p.Met9Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,656 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: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
IKZF1
NM_006060.6 missense
NM_006060.6 missense
Scores
1
5
7
Clinical Significance
Conservation
PhyloP100: 6.94
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 -6 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, IKZF1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19210106).
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000046 (7/152204) while in subpopulation AMR AF= 0.000458 (7/15284). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IKZF1 | NM_006060.6 | c.26T>C | p.Met9Thr | missense_variant | 2/8 | ENST00000331340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IKZF1 | ENST00000331340.8 | c.26T>C | p.Met9Thr | missense_variant | 2/8 | 1 | NM_006060.6 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248752Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135158
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461452Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4AN XY: 727046
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acute lymphoid leukemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostics Laboratory, National Institute of Medical Genomics | Sep 23, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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. This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 9 of the IKZF1 protein (p.Met9Thr). - |
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
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
MutationTaster
Benign
D;D;D;D;D;D;N;N;N;N
PrimateAI
Uncertain
T
Polyphen
0.094, 0.98, 0.33, 0.30
.;.;B;.;B;D;.;B;.;B;.;.;.;.;B;B;.
Vest4
0.51, 0.60, 0.52, 0.51, 0.53, 0.47, 0.52, 0.50, 0.49, 0.56, 0.51, 0.47
MutPred
Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);
MVP
0.36
MPC
1.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at