7-50327649-C-A

Variant names:

• chr7-50327649-C-A
• rs754640737
• NM_006060.6:c.52C>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_006060.6(IKZF1):​c.52C>A​(p.Pro18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36

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_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.52C>A	p.Pro18Thr	missense_variant	Exon 3 of 8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.52C>A	p.Pro18Thr	missense_variant	Exon 3 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460098 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the IKZF1 protein (p.Pro18Thr). This variant is present in population databases (rs754640737, gnomAD 0.006%). This missense change has been observed in individual(s) with Acute Lymphoblastic Leukemia (PMID: 29681510). ClinVar contains an entry for this variant (Variation ID: 1972179). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect IKZF1 function (PMID: 29681510). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;D;.;D;T;T;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;D;D;.;D;D;D;D;.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	.;.;.;.;N;D;.;N;N;N;N;N;N;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	.;.;.;.;D;D;.;D;D;D;D;D;D;.;D
Sift4G	Benign	0.28	.;.;.;.;T;D;T;T;T;T;T;T;T;.;D
Polyphen		0.52, 1.0, 0.58	.;.;P;.;P;D;.;P;.;D;.;P;D;.;.
Vest4		0.55, 0.57, 0.64, 0.53, 0.50, 0.68, 0.64, 0.53, 0.68
MutPred		0.22		Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);Gain of phosphorylation at P18 (P = 0.0034);.;
MVP		0.49
MPC		1.7
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.37

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: rs754640737; hg19: chr7-50367245;