Genetic Variant IKZF1:c.-15+6G>C (chr7-50304536-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001410879.1(IKZF1):c.-15+6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 149,798 control chromosomes in the GnomAD database, including 9,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.34 ( 9098 hom., cov: 32)

Exomes 𝑓: 0.32 ( 8 hom. )

Consequence

IKZF1
NM_001410879.1 splice_region, intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.925

Variant links:

Genes affected

IKZF1 (HGNC:13176): (IKAROS family zinc finger 1) This gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The expression of this protein is restricted to the fetal and adult hemo-lymphopoietic system, and it functions as a regulator of lymphocyte differentiation. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. Most isoforms share a common C-terminal domain, which contains two zinc finger motifs that are required for hetero- or homo-dimerization, and for interactions with other proteins. The isoforms, however, differ in the number of N-terminal zinc finger motifs that bind DNA and in nuclear localization signal presence, resulting in members with and without DNA-binding properties. Only a few isoforms contain the requisite three or more N-terminal zinc motifs that confer high affinity binding to a specific core DNA sequence element in the promoters of target genes. The non-DNA-binding isoforms are largely found in the cytoplasm, and are thought to function as dominant-negative factors. Overexpression of some dominant-negative isoforms have been associated with B-cell malignancies, such as acute lymphoblastic leukemia (ALL). [provided by RefSeq, May 2014]

IKZF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 7-50304536-G-C is Benign according to our data. Variant chr7-50304536-G-C is described in ClinVar as [Benign]. Clinvar id is 1235528.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6 link	c.-401G>C		upstream_gene_variant		ENST00000331340.8	NP_006051.1	Q13422-1R9R4D9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8 link	c.-401G>C		upstream_gene_variant		1	NM_006060.6	ENSP00000331614.3		Q13422-1

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

50954

AN:

149538

Hom.:

9082

Cov.:

show subpopulations

Gnomad AFR

AF:

0.369

Gnomad AMI

AF:

0.297

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.539

Gnomad SAS

AF:

0.392

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.243

Gnomad NFE

AF:

0.299

Gnomad OTH

AF:

0.326

GnomAD4 exome

AF:

0.316

AC:

AN:

152

Hom.:

AF XY:

0.295

AC XY:

AN XY:

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

Gnomad4 AMR exome

AF:

0.500

AC:

AN:

Gnomad4 ASJ exome

AC:

AN:

Gnomad4 EAS exome

AF:

1.00

AC:

AN:

Gnomad4 SAS exome

AF:

0.367

AC:

AN:

Gnomad4 FIN exome

AC:

AN:

Gnomad4 NFE exome

AF:

0.196

AC:

AN:

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.341

AC:

51022

AN:

149646

Hom.:

9098

Cov.:

AF XY:

0.343

AC XY:

25053

AN XY:

73040

show subpopulations

Gnomad4 AFR

AF:

0.369

AC:

0.368613

AN:

0.368613

Gnomad4 AMR

AF:

0.440

AC:

0.440003

AN:

0.440003

Gnomad4 ASJ

AF:

0.237

AC:

0.237347

AN:

0.237347

Gnomad4 EAS

AF:

0.539

AC:

0.538613

AN:

0.538613

Gnomad4 SAS

AF:

0.394

AC:

0.393599

AN:

0.393599

Gnomad4 FIN

AF:

0.275

AC:

0.275452

AN:

0.275452

Gnomad4 NFE

AF:

0.299

AC:

0.299365

AN:

0.299365

Gnomad4 OTH

AF:

0.329

AC:

0.329327

AN:

0.329327

Heterozygous variant carriers

1744

3489

5233

6978

8722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.173

Hom.:

332

Bravo

AF:

0.352

Asia WGS

AF:

0.497

AC:

1655

AN:

3334

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29292192) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

DANN

Benign

0.30

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.9

Splicing

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