Genetic Variant IKZF3:c.-40A>G (chr17-39864166-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_012481.5(IKZF3):c.-40A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,607,904 control chromosomes in the GnomAD database, including 205,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.52 ( 20836 hom., cov: 33)

Exomes 𝑓: 0.50 ( 184168 hom. )

Consequence

IKZF3
NM_012481.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.447

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 17-39864166-T-C is Benign according to our data. Variant chr17-39864166-T-C is described in ClinVar as [Benign]. Clinvar id is 2688021.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF3	NM_012481.5 link	c.-40A>G		5_prime_UTR_variant	Exon 1 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.-40A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_012481.5	ENSP00000344544.3		Q9UKT9-1

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78751

AN:

152052

Hom.:

20790

Cov.:

show subpopulations

Gnomad AFR

AF:

0.607

Gnomad AMI

AF:

0.671

Gnomad AMR

AF:

0.450

Gnomad ASJ

AF:

0.483

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.573

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.499

Gnomad OTH

AF:

0.488

GnomAD3 exomes

AF:

0.469

AC:

113843

AN:

242866

Hom.:

27836

AF XY:

0.469

AC XY:

62077

AN XY:

132346

show subpopulations

Gnomad AFR exome

AF:

0.607

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.252

Gnomad SAS exome

AF:

0.397

Gnomad FIN exome

AF:

0.573

Gnomad NFE exome

AF:

0.509

Gnomad OTH exome

AF:

0.485

GnomAD4 exome

AF:

0.499

AC:

726656

AN:

1455736

Hom.:

184168

Cov.:

AF XY:

0.496

AC XY:

359011

AN XY:

724392

show subpopulations

Gnomad4 AFR exome

AF:

0.610

Gnomad4 AMR exome

AF:

0.390

Gnomad4 ASJ exome

AF:

0.491

Gnomad4 EAS exome

AF:

0.264

Gnomad4 SAS exome

AF:

0.402

Gnomad4 FIN exome

AF:

0.563

Gnomad4 NFE exome

AF:

0.514

Gnomad4 OTH exome

AF:

0.486

GnomAD4 genome

AF:

0.518

AC:

78860

AN:

152168

Hom.:

20836

Cov.:

AF XY:

0.518

AC XY:

38505

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.607

Gnomad4 AMR

AF:

0.451

Gnomad4 ASJ

AF:

0.483

Gnomad4 EAS

AF:

0.269

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.573

Gnomad4 NFE

AF:

0.499

Gnomad4 OTH

AF:

0.486

Alfa

AF:

0.438

Hom.:

2770

Bravo

AF:

0.506

Asia WGS

AF:

0.421

AC:

1462

AN:

3474

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 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.83

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