17-39864166-T-C

Variant names:

• chr17-39864166-T-C
• rs1453559
• ENST00000293068.9:n.-40A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000293068.9(IKZF3):​n.-40A>G variant causes a non coding transcript exon 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 ENST00000293068.9 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.447
• Publications: 47 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 -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 VariationId 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	c.-40A>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000346872.8	NP_036613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF3	ENST00000346872.8	c.-40A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_012481.5	ENSP00000344544.3

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78751 AN: 152052 Hom.: 20790 Cov.: 33

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

GnomAD2 exomes AF: 0.469 AC: 113843 AN: 242866 AF XY: 0.469

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 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.: 34 AF XY: 0.496 AC XY: 359011 AN XY: 724392

African (AFR) AF: 0.610 AC: 19889 AN: 32580

American (AMR) AF: 0.390 AC: 17274 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12757 AN: 25960

East Asian (EAS) AF: 0.264 AC: 10311 AN: 39088

South Asian (SAS) AF: 0.402 AC: 34547 AN: 86016

European-Finnish (FIN) AF: 0.563 AC: 29882 AN: 53108

Middle Eastern (MID) AF: 0.512 AC: 2905 AN: 5670

European-Non Finnish (NFE) AF: 0.514 AC: 569862 AN: 1108984

Other (OTH) AF: 0.486 AC: 29229 AN: 60094

GnomAD4 genome AF: 0.518 AC: 78860 AN: 152168 Hom.: 20836 Cov.: 33 AF XY: 0.518 AC XY: 38505 AN XY: 74404

African (AFR) AF: 0.607 AC: 25215 AN: 41528

American (AMR) AF: 0.451 AC: 6890 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1675 AN: 3468

East Asian (EAS) AF: 0.269 AC: 1392 AN: 5166

South Asian (SAS) AF: 0.403 AC: 1946 AN: 4824

European-Finnish (FIN) AF: 0.573 AC: 6079 AN: 10612

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.499 AC: 33890 AN: 67966

Other (OTH) AF: 0.486 AC: 1027 AN: 2112

Alfa AF: 0.443 Hom.: 2917

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

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	14
DANN	Benign	0.83
PhyloP100		-0.45
PromoterAI		-0.072	Neutral
Mutation Taster		=299/1	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: rs1453559; hg19: chr17-38020419; COSMIC: COSV53099316; COSMIC: COSV53099316;