7-50319072-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_006060.6(IKZF1):c.11A>T(p.Asp4Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,304 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. D4Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

IKZF1
NM_006060.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6 link	c.11A>T	p.Asp4Val	missense_variant	Exon 2 of 8	ENST00000331340.8	NP_006051.1	Q13422-1R9R4D9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8 link	c.11A>T	p.Asp4Val	missense_variant	Exon 2 of 8	1	NM_006060.6	ENSP00000331614.3		Q13422-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461304

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726956

show subpopulations

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 01, 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 valine, which is neutral and non-polar, at codon 4 of the IKZF1 protein (p.Asp4Val). 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

0.18

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

.;.;T;.;T;T;T;.;.;.;.;.;T;T;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;.;D;D;D;.;D;D;D;T;T;T;D;.;D

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.43

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

.;.;.;.;N;D;.;N;N;D;N;D;N;.;N;D;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

.;.;.;.;D;D;.;D;D;D;D;D;D;.;D;D;.

Sift4G

Uncertain

0.0030

.;.;.;.;D;D;D;D;D;D;D;T;T;T;D;D;.

Polyphen

1.0, 1.0, 0.99, 0.93

.;.;D;.;D;D;.;D;.;P;.;.;.;.;D;P;.

Vest4

0.36, 0.61, 0.53, 0.36, 0.33, 0.58, 0.49, 0.36, 0.41, 0.59, 0.36, 0.58

MutPred

0.37

Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);Gain of catalytic residue at D4 (P = 0.2123);

MVP

0.42

MPC

1.8

ClinPred

0.99

GERP RS

5.9

Varity_R

0.24

gMVP

0.33

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over