NM_006060.6:c.814G>A

Variant names:

• chr7-50391827-G-A
• rs778820674
• NM_006060.6:c.814G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP2 PP5 BP4 BS2

The NM_006060.6(IKZF1):​c.814G>A​(p.Ala272Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.88
• Publications: 5 publications found

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]

IKZF1 Gene-Disease associations (from GenCC):

• pancytopenia due to IKZF1 mutations

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• autoimmune disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ENSG00000285165 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -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 pancytopenia due to IKZF1 mutations, autoimmune disease.
• PP5: Variant 7-50391827-G-A is Pathogenic according to our data. Variant chr7-50391827-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548705.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28837988). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.814G>A	p.Ala272Thr	missense_variant	Exon 7 of 8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.814G>A	p.Ala272Thr	missense_variant	Exon 7 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248700 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pancytopenia due to IKZF1 mutations Pathogenic:1

Jun 12, 2018

Immunogenetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The patient is a 15 years old male with a history of chronic refractory thrombocytopenia diagnosed at age of 6. He had episodes of low platelet count with diffuse petechiae and mucosal bleeding. He has normal T cell and B cell numbers, and normal immunoglobulin levels. However, he has increased double negative T cells (CD3+/CD4- CD8-). -

not specified Uncertain:1

Aug 03, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 272 of the IKZF1 protein (p.Ala272Thr). This variant is present in population databases (rs778820674, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 548705). 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. 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	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;T;.;.;.;T;.;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;.;D;.;D;D;D;D;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
PhyloP100		5.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	.;.;N;N;N;.;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.31	.;.;T;T;T;.;.;T;T
Sift4G	Benign	0.34	.;.;T;T;T;T;T;T;T
Polyphen		0.32, 0.83, 0.45	.;B;B;P;B;.;.;P;B
Vest4		0.33, 0.42, 0.39, 0.32, 0.29, 0.39
MutPred		0.23		.;Gain of phosphorylation at A272 (P = 0.045);Gain of phosphorylation at A272 (P = 0.045);.;.;.;.;.;.;
MVP		0.40
MPC		0.94
ClinPred		0.90	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.19
gMVP		0.43
Mutation Taster		=59/41	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs778820674; hg19: chr7-50459525; COSMIC: COSV58781357;