7-50382702-A-G

Variant names:

• chr7-50382702-A-G
• rs1131690788
• NM_006060.6:c.584A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_006060.6(IKZF1):​c.584A>G​(p.His195Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 7-50382702-A-G is Pathogenic according to our data. Variant chr7-50382702-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428611.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pancytopenia due to IKZF1 mutations Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Immunogenetics Laboratory, Johns Hopkins All Children's Hospital

Apr 05, 2017

Mutations in the transcription factor IKAROS (encoded by IKZF1) cause an autosomal dominant antibody deficiency (infections, progressive loss of B cells and immunoglobulins [Ig]). Cytopenia and leukemia may occur. We report a teenager who presents with chronic severe immune thrombocytopenia (ITP) and low serum IgG, IgA, and IgM since age 3. His mother also had low IgG and at age 23 had ITP requiring splenectomy. Neither had frequent infections. Patient and his mother had a novel heterozygous missense mutation in the DNA binding motif zinc finger 3 of IKZF1 (c.584A>G, p.His195Arg). In vitro studies of mutant IKAROS showed loss of characteristic pericentromeric DNA-binding (arrow), consistent with previous findings of other pathogenic mutations (H167R) in IKZF1. IKAROS deficiency may present with ITP in the absence of infections. For ITP patients, we recommend serum Ig screening and evaluation for antibody defects. Identifying the genetic diagnosis in these cases can help anticipate complications in patients and their families. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;.;D;D;D;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.2	.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;.;D;D;D;T;D;D
Sift4G	Pathogenic	0.0	.;.;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;D;D;.;D;D
Vest4		0.97, 0.94, 0.97, 0.97, 0.94, 0.97
MutPred		0.87		.;Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);.;Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);.;
MVP		0.94
MPC		2.3
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs1131690788; hg19: chr7-50450400;