NM_012481.5:c.1075C>G

Variant names:

• chr17-39766245-G-C
• rs201230036
• NM_012481.5:c.1075C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_012481.5(IKZF3):​c.1075C>G​(p.Leu359Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: IKZF3 NM_012481.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.528
• Publications: 1 publications found

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]

IKZF3 Gene-Disease associations (from GenCC):

• immunodeficiency 84

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056161165).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012481.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF3	NM_012481.5	MANE Select	c.1075C>G	p.Leu359Val	missense	Exon 8 of 8	NP_036613.2
	IKZF3	NM_001257408.2		c.973C>G	p.Leu325Val	missense	Exon 7 of 7	NP_001244337.1	Q9UKT9-7
	IKZF3	NM_183229.3		c.958C>G	p.Leu320Val	missense	Exon 7 of 7	NP_899052.1	Q9UKT9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF3	ENST00000346872.8	TSL:1 MANE Select	c.1075C>G	p.Leu359Val	missense	Exon 8 of 8	ENSP00000344544.3	Q9UKT9-1
	IKZF3	ENST00000535189.5	TSL:1	c.973C>G	p.Leu325Val	missense	Exon 7 of 7	ENSP00000438972.1	Q9UKT9-7
	IKZF3	ENST00000439167.6	TSL:1	c.856C>G	p.Leu286Val	missense	Exon 6 of 6	ENSP00000403776.2	Q9UKT9-8

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251398 AF XY: 0.0000515

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.000133 AC XY: 97 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000164 AC: 182 AN: 1112010

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.94
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.53
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.019
Sift	Benign	0.18	T
Sift4G	Benign	0.55	T
Polyphen		0.014	B
Vest4		0.069
MVP		0.28
MPC		0.62
ClinPred		0.039	T
GERP RS		1.4
Varity_R		0.055
gMVP		0.17
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs201230036; hg19: chr17-37922498;