Genetic Variant IKZF4:p.His23Tyr (chr12-56021560-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022465.4(IKZF4):c.67C>T(p.His23Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000326 in 1,607,462 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

IKZF4
NM_022465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.30

Variant links:

Genes affected

IKZF4 (HGNC:13179): (IKAROS family zinc finger 4) Members of the Ikaros (ZNFN1A1; MIM 603023) family of transcription factors, which includes Eos, are expressed in lymphocytes and are implicated in the control of lymphoid development.[supplied by OMIM, Jul 2002]

IKZF4 links:

LOC105369781 (HGNC:):

LOC105369781 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03328252).

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF4	NM_022465.4 link	c.67C>T	p.His23Tyr	missense_variant	Exon 1 of 8	ENST00000547167.6	NP_071910.3	Q9H2S9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF4	ENST00000547167.6 link	c.67C>T	p.His23Tyr	missense_variant	Exon 1 of 8	1	NM_022465.4	ENSP00000448419.1		Q9H2S9-1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000853

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000289

AC:

AN:

234910

Hom.:

AF XY:

0.000212

AC XY:

AN XY:

127646

show subpopulations

Gnomad AFR exome

AF:

0.000287

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000102

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.000699

GnomAD4 exome

AF:

0.000330

AC:

481

AN:

1455516

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

219

AN XY:

723412

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000639

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000949

Gnomad4 NFE exome

AF:

0.000376

Gnomad4 OTH exome

AF:

0.000449

GnomAD4 genome

AF:

0.000283

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000852

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000379

Hom.:

Bravo

AF:

0.000423

ESP6500AA

AF:

0.000253

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.67C>T (p.H23Y) alteration is located in exon 1 (coding exon 1) of the IKZF4 gene. This alteration results from a C to T substitution at nucleotide position 67, causing the histidine (H) at amino acid position 23 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

-0.057

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.60

.;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.033

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.76

N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.29

N;.;N

REVEL

Benign

0.060

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

0.22

B;B;B

Vest4

0.50

MVP

0.26

MPC

0.13

ClinPred

0.020

GERP RS

5.0

Varity_R

0.18

gMVP

0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over