rs770551610
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3PM1PM2PM5PP2PP5_Moderate
The NM_006060.6(IKZF1):c.485G>A(p.Arg162Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004295198: Experimental studies have shown that this missense change affects IKZF1 function (PMID:26981933, 27939403, 31057532).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162W) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
IKZF1
NM_006060.6 missense
NM_006060.6 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 10.0
Publications
14 publications found
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]
IKZF1 Gene-Disease associations (from GenCC):
- pancytopenia due to IKZF1 mutationsInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- autoimmune diseaseInheritance: AD Classification: MODERATE Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 13 ACMG points.
PS3
PS3 evidence extracted from ClinVar submissions: SCV004295198: Experimental studies have shown that this missense change affects IKZF1 function (PMID: 26981933, 27939403, 31057532).
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006060.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-50382602-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 827710.
PP2
Missense variant in the IKZF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.3753 (above the threshold of 3.09). Trascript score misZ: 3.423 (above the threshold of 3.09). GenCC associations: The gene is linked to autoimmune disease, pancytopenia due to IKZF1 mutations.
PP5
Variant 7-50382603-G-A is Pathogenic according to our data. Variant chr7-50382603-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224779.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006060.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IKZF1 | MANE Select | c.485G>A | p.Arg162Gln | missense | Exon 5 of 8 | NP_006051.1 | Q13422-1 | ||
| IKZF1 | c.545G>A | p.Arg182Gln | missense | Exon 6 of 9 | NP_001397808.1 | A0A8V8TNQ0 | |||
| IKZF1 | c.485G>A | p.Arg162Gln | missense | Exon 5 of 7 | NP_001207694.1 | Q13422-7 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IKZF1 | TSL:1 MANE Select | c.485G>A | p.Arg162Gln | missense | Exon 5 of 8 | ENSP00000331614.3 | Q13422-1 | ||
| IKZF1 | TSL:1 | c.485G>A | p.Arg162Gln | missense | Exon 5 of 7 | ENSP00000352123.5 | Q13422-7 | ||
| IKZF1 | TSL:1 | c.485G>A | p.Arg162Gln | missense | Exon 5 of 7 | ENSP00000413025.1 | Q13422-7 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152168Hom.: 0 Cov.: 33
GnomAD3 genomes
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33
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GnomAD2 exomes AF: 0.00 AC: 0AN: 248502 AF XY: 0.00
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461442Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726996 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461442
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Cov.:
31
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726996
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86238
European-Finnish (FIN)
AF:
AC:
0
AN:
53218
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111826
Other (OTH)
AF:
AC:
0
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
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Allele balance
GnomAD4 genome 0.00 AC: 0AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74328
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
152168
Hom.:
Cov.:
33
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AC XY:
0
AN XY:
74328
African (AFR)
AF:
AC:
0
AN:
41440
American (AMR)
AF:
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5194
South Asian (SAS)
AF:
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68028
Other (OTH)
AF:
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0
AN:
2090
Alfa
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1
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
1
-
-
Pancytopenia due to IKZF1 mutations (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0559)
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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
Publications
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