17-39766411-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012481.5(IKZF3):c.909G>T(p.Met303Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKZF3 NM_012481.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

Genes affected

IKZF3 (HGNC:13178): (IKAROS family zinc finger 3) This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This gene product is a transcription factor that is important in the regulation of B lymphocyte proliferation and differentiation. Both Ikaros and Aiolos can participate in chromatin remodeling. Regulation of gene expression in B lymphocytes by Aiolos is complex as it appears to require the sequential formation of Ikaros homodimers, Ikaros/Aiolos heterodimers, and Aiolos homodimers. Several alternative transcripts encoding different isoforms have been described, as well as some non-protein coding variants. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18703061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKZF3	NM_012481.5	c.909G>T	p.Met303Ile	missense_variant	8/8	ENST00000346872.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKZF3	ENST00000346872.8	c.909G>T	p.Met303Ile	missense_variant	8/8	1	NM_012481.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Jun 30, 2022

The c.909G>T (p.M303I) alteration is located in exon 8 (coding exon 8) of the IKZF3 gene. This alteration results from a G to T substitution at nucleotide position 909, causing the methionine (M) at amino acid position 303 to be replaced by an isoleucine (I). 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	0.80
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.97
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.092
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;D;B;B;B;B;B;B;.;B;B;B;B;B
Vest4		0.30
MutPred		0.49		Loss of disorder (P = 0.1041);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.12
MPC		0.67
ClinPred		0.74	D
GERP RS		5.0
Varity_R		0.13
gMVP		0.57

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.

Other links and lift over

hg19: chr17-37922664;