7-50382603-G-T

Variant names:

• chr7-50382603-G-T
• rs770551610
• NM_006060.6:c.485G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_006060.6(IKZF1):​c.485G>T​(p.Arg162Leu) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 10.0

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 7 ACMG points.

• PM1: In a site Required for both pericentromeric heterochromatin localization and complete DNA binding (size 0) in uniprot entity IKZF1_HUMAN
• 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, 0.779
• PP5: Variant 7-50382603-G-T is Pathogenic according to our data. Variant chr7-50382603-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224778.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.485G>T	p.Arg162Leu	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.485G>T	p.Arg162Leu	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Feb 14, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (R162W) has been reported in association with IKZF1-related immune disorder and/or hematologic disease (Hoshino et al., 2016; Winer et al., 2020); This variant is associated with the following publications: (PMID: 35853737, 29461212, 27316315, 26981933, 27939403, 10970879, 32084258) -

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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. This variant disrupts the Arg162 amino acid residue in IKZF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26981933). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects IKZF1 function (PMID: 26981933). ClinVar contains an entry for this variant (Variation ID: 224778). This missense change has been observed in individual(s) with clinical features of IKZF1-related conditions (PMID: 26981933). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 162 of the IKZF1 protein (p.Arg162Leu). -

Pancytopenia due to IKZF1 mutations Pathogenic:1

Aug 25, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D;D;T;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;D;D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.2	.;.;D;.;D;D;D;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;.;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;.;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;.;D;D;.;D;D
Vest4		0.93, 0.92, 0.92, 0.96, 0.92, 0.92, 0.96
MutPred		0.51		.;Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);.;Loss of MoRF binding (P = 0.0492);.;Loss of MoRF binding (P = 0.0492);Loss of MoRF binding (P = 0.0492);.;
MVP		0.62
MPC		2.3
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.92

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: rs770551610; hg19: chr7-50450301;