7-50327661-G-A

Position:

• chr7-50327661-G-A

Variant summary

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

The NM_006060.6(IKZF1):​c.64G>A​(p.Asp22Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,460,900 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: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 8.92

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 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). GenCC has associacion of gene with autoimmune disease, pancytopenia due to IKZF1 mutations.
• PP5: Variant 7-50327661-G-A is Pathogenic according to our data. Variant chr7-50327661-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548932.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29674098). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.64G>A	p.Asp22Asn	missense_variant	3/8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.64G>A	p.Asp22Asn	missense_variant	3/8	1	NM_006060.6	ENSP00000331614	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000810 AC: 2 AN: 247050 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134334

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460900 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2023	This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 22 of the IKZF1 protein (p.Asp22Asn). This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 548932). -

Pancytopenia due to IKZF1 mutations Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Immunogenetics Laboratory, Johns Hopkins All Children's Hospital

Jun 11, 2018

This is a novel low frequency variant (0.00082%). The nucleotide is highly conserved and the amino acid is moderately conserved. Prediction programs SIFT predicted deleterious (score: 0.03, median: 4.32), Mutation taster predicted disease causing (p-value: 1), and PolyPhen-2 predicted probably damaging (score 1.000). Germline IKZF1 mutations have been identified recently as a cause of common variable immunodeficiency and dysgammaglobulinemia through IKAROS haploinsufficiency (Bogaert 2018). They are autosomal dominantly inherited. This patient has the characteristics of IKZF1 deficiency, such as autoimmune disease, frequent infections, hematopoietic abnormality, and dysgammaglobinemia. No mutations are identified in other known CVID genes and 250 primary immunodeficiency genes in this patient. It is very likely that this variant is the cause of the patient’s disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;T;.;T;T;T;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;D;D;.;D;D;D;D;.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	.;.;.;.;N;D;.;N;N;N;N;N;N;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	.;.;.;.;D;D;.;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.045	.;.;.;.;D;D;T;T;T;D;T;T;D;.;D
Polyphen		1.0, 0.98, 0.97	.;.;D;.;D;D;.;D;.;D;.;D;D;.;.
Vest4		0.36, 0.39, 0.47, 0.33, 0.37, 0.37, 0.41, 0.33
MutPred		0.21		Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);Gain of glycosylation at S21 (P = 0.1148);.;
MVP		0.45
MPC		1.9
ClinPred		0.91	D
GERP RS		5.9
Varity_R		0.11
gMVP		0.099

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: rs1245618829; hg19: chr7-50367257; COSMIC: COSV58784478;