12-56025101-G-C

Variant names:

• chr12-56025101-G-C
• NM_022465.4:c.229G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022465.4(IKZF4):​c.229G>C​(p.Gly77Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IKZF4 NM_022465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.45

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]

LOC105369781 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF4	NM_022465.4	c.229G>C	p.Gly77Arg	missense_variant	Exon 3 of 8	ENST00000547167.6	NP_071910.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF4	ENST00000547167.6	c.229G>C	p.Gly77Arg	missense_variant	Exon 3 of 8	1	NM_022465.4	ENSP00000448419.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720850

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229G>C (p.G77R) alteration is located in exon 3 (coding exon 3) of the IKZF4 gene. This alteration results from a G to C substitution at nucleotide position 229, causing the glycine (G) at amino acid position 77 to be replaced by an arginine (R). 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;.;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N;.;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;.;D;D
Sift4G	Uncertain	0.025	D;D;D;T
Polyphen		1.0	D;D;D;D
Vest4		0.85
MutPred		0.26		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;
MVP		0.64
MPC		0.21
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.31
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56418885;