chr7-50327661-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP2PP5BP4BS1_SupportingBS2
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
Consequence
NM_006060.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000810 AC: 2AN: 247050Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134334
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460900Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726704
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
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). 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 0.002%). 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). -
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at