rs1245618829
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP5BP4BS2
The NM_006060.6(IKZF1):c.64G>A(p.Asp22Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,460,900 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
IKZF1
NM_006060.6 missense
NM_006060.6 missense
Scores
2
4
7
Clinical Significance
Conservation
PhyloP100: 8.92
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 Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, IKZF1
PP5
?
Variant 7-50327661-G-A is Pathogenic according to our data. Variant chr7-50327661-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548932.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.29674098). . Strength limited to SUPPORTING due to the PP5.
BS2
?
High AC in GnomAdExome4 at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IKZF1 | NM_006060.6 | c.64G>A | p.Asp22Asn | missense_variant | 3/8 | ENST00000331340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IKZF1 | ENST00000331340.8 | c.64G>A | p.Asp22Asn | missense_variant | 3/8 | 1 | NM_006060.6 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000810 AC: 2AN: 247050Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134334
GnomAD3 exomes
AF:
AC:
2
AN:
247050
Hom.:
AF XY:
AC XY:
0
AN XY:
134334
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460900Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726704
GnomAD4 exome
AF:
AC:
22
AN:
1460900
Hom.:
Cov.:
30
AF XY:
AC XY:
11
AN XY:
726704
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
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 22 of the IKZF1 protein (p.Asp22Asn). This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 548932). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Pancytopenia due to IKZF1 mutations Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Immunogenetics Laboratory, Johns Hopkins All Children's Hospital | Jun 11, 2018 | This is a novel low frequency variant (0.00082%). The nucleotide is highly conserved and the amino acid is moderately conserved. Prediction programs SIFT predicted deleterious (score: 0.03, median: 4.32), Mutation taster predicted disease causing (p-value: 1), and PolyPhen-2 predicted probably damaging (score 1.000). Germline IKZF1 mutations have been identified recently as a cause of common variable immunodeficiency and dysgammaglobulinemia through IKAROS haploinsufficiency (Bogaert 2018). They are autosomal dominantly inherited. This patient has the characteristics of IKZF1 deficiency, such as autoimmune disease, frequent infections, hematopoietic abnormality, and dysgammaglobinemia. No mutations are identified in other known CVID genes and 250 primary immunodeficiency genes in this patient. It is very likely that this variant is the cause of the patient’s disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
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
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
Uncertain
T
Polyphen
1.0, 0.98, 0.97
.;.;D;.;D;D;.;D;.;D;.;D;D;.;.
Vest4
0.36, 0.39, 0.47, 0.33, 0.37, 0.37, 0.41, 0.33
MutPred
Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);.;
MVP
0.45
MPC
1.9
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