7-50327647-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_006060.6(IKZF1):​c.50G>A​(p.Ser17Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,938 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: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IKZF1
NM_006060.6 missense

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.92
Variant links:
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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=0.32809967).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IKZF1NM_006060.6 linkuse as main transcriptc.50G>A p.Ser17Asn missense_variant 3/8 ENST00000331340.8 NP_006051.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IKZF1ENST00000331340.8 linkuse as main transcriptc.50G>A p.Ser17Asn missense_variant 3/81 NM_006060.6 ENSP00000331614 A1Q13422-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459938
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726106
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 02, 2023In 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. This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 17 of the IKZF1 protein (p.Ser17Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.094
T
BayesDel_noAF
Benign
-0.37
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
.;.;T;.;T;T;T;.;.;.;.;.;.;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;.;.;D;D;D;.;D;D;D;D;.;D
M_CAP
Benign
0.068
D
MetaRNN
Benign
0.33
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.2
.;.;.;.;N;D;.;N;N;N;N;N;N;.
REVEL
Benign
0.19
Sift
Uncertain
0.0020
.;.;.;.;D;D;.;D;D;D;D;D;D;.
Sift4G
Benign
0.075
.;.;.;.;T;D;D;T;D;T;T;T;T;.
Polyphen
0.99, 1.0, 0.83, 1.0
.;.;D;.;D;D;.;P;.;D;.;P;D;.
Vest4
0.57, 0.65, 0.61, 0.56, 0.46, 0.66, 0.64, 0.56, 0.66
MutPred
0.19
Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);Loss of phosphorylation at S17 (P = 0.0019);
MVP
0.38
MPC
1.7
ClinPred
0.98
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.37
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-50367243; COSMIC: COSV100498136; COSMIC: COSV100498136; API