rs6964823

Positions:

• chr7-50392398-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006060.6(IKZF1):​c.850+535G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 151,110 control chromosomes in the GnomAD database, including 15,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (15201 hom., cov: 30)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.52

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKZF1	NM_006060.6	c.850+535G>A		intron_variant		ENST00000331340.8
LOC124901631	XR_007060322.1	n.82+1478C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKZF1	ENST00000331340.8	c.850+535G>A		intron_variant		1	NM_006060.6	A1
	ENST00000644669.1	n.289+1478C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67442 AN: 151004 Hom.: 15192 Cov.: 30

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.461

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.446 AC: 67467 AN: 151110 Hom.: 15201 Cov.: 30 AF XY: 0.437 AC XY: 32232 AN XY: 73806

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.496

Gnomad4 OTH AF: 0.458

Alfa AF: 0.483 Hom.: 23039

Bravo AF: 0.446

Asia WGS AF: 0.316 AC: 1102 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.029
DANN	Benign	0.11

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

Other links and lift over

dbSNP: rs6964823; hg19: chr7-50460096;