7-50319071-G-T

Variant names:

• chr7-50319071-G-T
• rs1792377766
• NM_006060.6:c.10G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006060.6(IKZF1):​c.10G>T​(p.Asp4Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.67

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.10G>T	p.Asp4Tyr	missense_variant	Exon 2 of 8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.10G>T	p.Asp4Tyr	missense_variant	Exon 2 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461244 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 4 of the IKZF1 protein (p.Asp4Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. 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. 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	0.25
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;D;.;D;T;T;.;.;.;.;.;T;T;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;D;D;.;D;D;D;T;T;T;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	.;.;.;.;N;D;.;N;N;D;D;D;N;.;N;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	.;.;.;.;D;D;.;D;D;D;D;D;D;.;D;D;.
Sift4G	Uncertain	0.0020	.;.;.;.;D;D;D;D;D;D;D;D;T;T;D;D;.
Polyphen		1.0, 1.0, 1.0	.;.;D;.;D;D;.;D;.;D;.;.;.;.;D;D;.
Vest4		0.39, 0.58, 0.53, 0.35, 0.34, 0.56, 0.48, 0.41, 0.42, 0.57, 0.35, 0.56
MutPred		0.41		Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);Gain of phosphorylation at D4 (P = 0.0016);
MVP		0.40
MPC		2.2
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.38

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: rs1792377766; hg19: chr7-50358667; COSMIC: COSV58786061;