7-50327671-A-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_006060.6(IKZF1):c.74A>T(p.Asp25Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,394 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 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
IKZF1
NM_006060.6 missense
NM_006060.6 missense
Scores
2
4
12
Clinical Significance
Conservation
PhyloP100: 8.31
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 -5 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKZF1. . Gene score misZ 3.3753 (greater than the threshold 3.09). Trascript score misZ 3.423 (greater than threshold 3.09). GenCC has associacion of gene with autoimmune disease, pancytopenia due to IKZF1 mutations.
BP4
Computational evidence support a benign effect (MetaRNN=0.23696452).
BS2
High AC in GnomAdExome4 at 93 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IKZF1 | NM_006060.6 | c.74A>T | p.Asp25Val | missense_variant | 3/8 | ENST00000331340.8 | NP_006051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IKZF1 | ENST00000331340.8 | c.74A>T | p.Asp25Val | missense_variant | 3/8 | 1 | NM_006060.6 | ENSP00000331614 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152088Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000808 AC: 2AN: 247616Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134636
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GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461306Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54AN XY: 726884
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74294
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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 | Labcorp Genetics (formerly Invitae), Labcorp | Jun 20, 2023 | 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 disruptive. 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 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 25 of the IKZF1 protein (p.Asp25Val). - |
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
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;.;D;D;D;.;D;D;D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Benign
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;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
.;.;.;.;N;D;.;N;N;N;N;N;N;.;D
REVEL
Benign
Sift
Uncertain
.;.;.;.;D;D;.;D;D;T;D;D;T;.;D
Sift4G
Benign
.;.;.;.;T;D;D;T;D;D;T;T;D;.;D
Polyphen
0.81, 0.93, 0.92, 0.0060
.;.;P;.;P;P;.;P;.;B;.;P;B;.;.
Vest4
0.57, 0.42, 0.55, 0.55, 0.56, 0.58, 0.64, 0.55
MutPred
Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);Gain of glycosylation at S21 (P = 0.1168);.;
MVP
0.43
MPC
2.2
ClinPred
D
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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