chr7-50304536-G-C

Position:

• chr7-50304536-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001410879.1(IKZF1):​c.-15+6G>C variant causes a splice donor 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_donor_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.925

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
IKZF1	NM_001291839.2	c.-15+422G>C		intron_variant			NP_001278768.1
IKZF1	NM_001410879.1	c.-15+6G>C		splice_donor_region_variant, intron_variant			NP_001397808.1
IKZF1	XM_011515058.3	c.58+996G>C		intron_variant			XP_011513360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000642219.2	c.-15+177G>C		intron_variant				ENSP00000496655
IKZF1	ENST00000645066.1	c.-15+422G>C		intron_variant				ENSP00000494055
IKZF1	ENST00000698573.1	c.-15+422G>C		intron_variant				ENSP00000513804

Frequencies

GnomAD3 genomes AF: 0.341 AC: 50954 AN: 149538 Hom.: 9082 Cov.: 32

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: 48 AN: 152 Hom.: 8 AF XY: 0.295 AC XY: 26 AN XY: 88

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.367

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.341 AC: 51022 AN: 149646 Hom.: 9098 Cov.: 32 AF XY: 0.343 AC XY: 25053 AN XY: 73040

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.394

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.329

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2020

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	14
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

Other links and lift over

dbSNP: rs11761922; hg19: chr7-50344132;