NM_012481.5:c.1314C>T

Variant names:

• chr17-39766006-G-A
• rs907092
• NM_012481.5:c.1314C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_012481.5(IKZF3):​c.1314C>T​(p.Ser438Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,613,964 control chromosomes in the GnomAD database, including 162,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11444 hom., cov: 32)
  • Exomes 𝑓: 0.45 (151423 hom.)
• Consequence: IKZF3 NM_012481.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33
• Publications: 111 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.028).
• BP6: Variant 17-39766006-G-A is Benign according to our data. Variant chr17-39766006-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688057.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF3	NM_012481.5	c.1314C>T	p.Ser438Ser	synonymous_variant	Exon 8 of 8	ENST00000346872.8	NP_036613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF3	ENST00000346872.8	c.1314C>T	p.Ser438Ser	synonymous_variant	Exon 8 of 8	1	NM_012481.5	ENSP00000344544.3

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55207 AN: 152038 Hom.: 11441 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.353

GnomAD2 exomes AF: 0.406 AC: 101971 AN: 251380 AF XY: 0.413

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.452

Gnomad EAS exome AF: 0.269

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.450 AC: 657520 AN: 1461808 Hom.: 151423 Cov.: 54 AF XY: 0.448 AC XY: 325716 AN XY: 727202

African (AFR) AF: 0.152 AC: 5103 AN: 33478

American (AMR) AF: 0.328 AC: 14668 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11672 AN: 26136

East Asian (EAS) AF: 0.301 AC: 11952 AN: 39680

South Asian (SAS) AF: 0.372 AC: 32100 AN: 86254

European-Finnish (FIN) AF: 0.533 AC: 28492 AN: 53408

Middle Eastern (MID) AF: 0.351 AC: 2026 AN: 5768

European-Non Finnish (NFE) AF: 0.473 AC: 526430 AN: 1111976

Other (OTH) AF: 0.415 AC: 25077 AN: 60386

GnomAD4 genome AF: 0.363 AC: 55219 AN: 152156 Hom.: 11444 Cov.: 32 AF XY: 0.366 AC XY: 27244 AN XY: 74392

African (AFR) AF: 0.164 AC: 6827 AN: 41532

American (AMR) AF: 0.365 AC: 5580 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1548 AN: 3466

East Asian (EAS) AF: 0.286 AC: 1479 AN: 5180

South Asian (SAS) AF: 0.370 AC: 1784 AN: 4824

European-Finnish (FIN) AF: 0.543 AC: 5738 AN: 10574

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30826 AN: 67972

Other (OTH) AF: 0.351 AC: 742 AN: 2112

Alfa AF: 0.424 Hom.: 61655

Bravo AF: 0.336

Asia WGS AF: 0.360 AC: 1252 AN: 3478

EpiCase AF: 0.455

EpiControl AF: 0.450

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		1.3
Mutation Taster		=98/2	polymorphism (auto)

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: rs907092; hg19: chr17-37922259; COSMIC: COSV53099275;