12-56027917-G-A

Position:

• chr12-56027917-G-A

Variant summary

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

The NM_022465.4(IKZF4):​c.685G>A​(p.Ala229Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,972 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: IKZF4 NM_022465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98

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 (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/exons	MANE	Protein	UniProt
IKZF4	NM_022465.4	c.685G>A	p.Ala229Thr	missense_variant	5/8	ENST00000547167.6	NP_071910.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF4	ENST00000547167.6	c.685G>A	p.Ala229Thr	missense_variant	5/8	1	NM_022465.4	ENSP00000448419.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429972 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 707652

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.685G>A (p.A229T) alteration is located in exon 5 (coding exon 5) of the IKZF4 gene. This alteration results from a G to A substitution at nucleotide position 685, causing the alanine (A) at amino acid position 229 to be replaced by a threonine (T). 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	0.92
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;D;D;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D;.;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.28	N;N;N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.43
MutPred		0.32		Gain of disorder (P = 0.0891);Gain of disorder (P = 0.0891);Gain of disorder (P = 0.0891);.;
MVP		0.64
MPC		2.5
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.56
gMVP		0.66

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: rs1894278965; hg19: chr12-56421701;