7-50319068-G-A

Position:

• chr7-50319068-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006060.6(IKZF1):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKZF1. . Gene score misZ: 3.3753 (greater than the threshold 3.09). Trascript score misZ: 3.423 (greater than threshold 3.09). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. GenCC has associacion of the gene with autoimmune disease, pancytopenia due to IKZF1 mutations.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07470077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.7G>A	p.Ala3Thr	missense_variant	2/8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.7G>A	p.Ala3Thr	missense_variant	2/8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461054 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.23	.;.;T;.;T;T;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.073
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D;D;.;.;D;D;D;.;D;D;D;T;T;T;D;.;D
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.075	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.68	.;.;.;.;N;N;.;N;N;N;N;N;N;.;N;N;.
REVEL	Benign	0.042
Sift	Benign	0.78	.;.;.;.;T;T;.;T;T;T;T;T;T;.;T;T;.
Sift4G	Benign	0.63	.;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0, 0.88	.;.;B;.;B;P;.;B;.;B;.;.;.;.;B;B;.
Vest4		0.12, 0.11, 0.10, 0.10, 0.092, 0.090, 0.15, 0.052, 0.10, 0.078
MutPred		0.19		Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);Gain of phosphorylation at A3 (P = 0.0152);
MVP		0.21
MPC		0.91
ClinPred		0.71	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.13

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: rs1584438980; hg19: chr7-50358664;