Genetic Variant IKZF3:p.Ser438Ser (chr17-39766006-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.33

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 17-39766006-G-A is Benign according to our data. Variant chr17-39766006-G-A is described in ClinVar as [Benign]. Clinvar id 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 link	c.1314C>T	p.Ser438Ser	synonymous_variant	Exon 8 of 8	ENST00000346872.8	NP_036613.2	Q9UKT9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF3	ENST00000346872.8 link	c.1314C>T	p.Ser438Ser	synonymous_variant	Exon 8 of 8	1	NM_012481.5	ENSP00000344544.3		Q9UKT9-1

Frequencies

GnomAD3 genomes

AF:

0.363

AC:

55207

AN:

152038

Hom.:

11441

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.406

AC:

101971

AN:

251380

Hom.:

22028

AF XY:

0.413

AC XY:

56143

AN XY:

135858

show subpopulations

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 SAS exome

AF:

0.368

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.:

AF XY:

0.448

AC XY:

325716

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.152

Gnomad4 AMR exome

AF:

0.328

Gnomad4 ASJ exome

AF:

0.447

Gnomad4 EAS exome

AF:

0.301

Gnomad4 SAS exome

AF:

0.372

Gnomad4 FIN exome

AF:

0.533

Gnomad4 NFE exome

AF:

0.473

Gnomad4 OTH exome

AF:

0.415

GnomAD4 genome

AF:

0.363

AC:

55219

AN:

152156

Hom.:

11444

Cov.:

AF XY:

0.366

AC XY:

27244

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.164

Gnomad4 AMR

AF:

0.365

Gnomad4 ASJ

AF:

0.447

Gnomad4 EAS

AF:

0.286

Gnomad4 SAS

AF:

0.370

Gnomad4 FIN

AF:

0.543

Gnomad4 NFE

AF:

0.454

Gnomad4 OTH

AF:

0.351

Alfa

AF:

0.434

Hom.:

31742

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

LINK: link

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

DANN

Benign

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over