chr17-39829548-A-G

Variant names:

• chr17-39829548-A-G
• rs3816470
• NM_012481.5:c.62-60T>C

Variant summary

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

The NM_012481.5(IKZF3):​c.62-60T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,189,472 control chromosomes in the GnomAD database, including 166,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (22257 hom., cov: 33)
  • Exomes 𝑓: 0.52 (144388 hom.)
• Consequence: IKZF3 NM_012481.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.853
• 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=-0.68).
• BP6: Variant 17-39829548-A-G is Benign according to our data. Variant chr17-39829548-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF3	NM_012481.5	c.62-60T>C		intron_variant	Intron 2 of 7	ENST00000346872.8	NP_036613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF3	ENST00000346872.8	c.62-60T>C		intron_variant	Intron 2 of 7	1	NM_012481.5	ENSP00000344544.3

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81406 AN: 151990 Hom.: 22207 Cov.: 33

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.523 AC: 542601 AN: 1037364 Hom.: 144388 AF XY: 0.519 AC XY: 276528 AN XY: 533192

African (AFR) AF: 0.638 AC: 15820 AN: 24808

American (AMR) AF: 0.416 AC: 16864 AN: 40586

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 11980 AN: 22900

East Asian (EAS) AF: 0.274 AC: 9912 AN: 36180

South Asian (SAS) AF: 0.424 AC: 31715 AN: 74716

European-Finnish (FIN) AF: 0.577 AC: 28573 AN: 49544

Middle Eastern (MID) AF: 0.535 AC: 2551 AN: 4770

European-Non Finnish (NFE) AF: 0.544 AC: 401619 AN: 737742

Other (OTH) AF: 0.511 AC: 23567 AN: 46118

GnomAD4 genome AF: 0.536 AC: 81517 AN: 152108 Hom.: 22257 Cov.: 33 AF XY: 0.534 AC XY: 39689 AN XY: 74344

African (AFR) AF: 0.622 AC: 25799 AN: 41482

American (AMR) AF: 0.461 AC: 7047 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1779 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1412 AN: 5186

South Asian (SAS) AF: 0.415 AC: 2003 AN: 4822

European-Finnish (FIN) AF: 0.580 AC: 6122 AN: 10558

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35523 AN: 67978

Other (OTH) AF: 0.500 AC: 1057 AN: 2116

Alfa AF: 0.510 Hom.: 4734

Bravo AF: 0.525

Asia WGS AF: 0.434 AC: 1508 AN: 3478

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	-0.68
CADD	Benign	4.9
DANN	Benign	0.69
PhyloP100		-0.85
Mutation Taster		=100/0	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: rs3816470; hg19: chr17-37985801; COSMIC: COSV53099307;