rs6954833

Positions:

• chr7-50390748-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.716-981G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 152,178 control chromosomes in the GnomAD database, including 43,502 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 0.75 (43502 hom., cov: 33)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.716-981G>A		intron_variant		ENST00000331340.8	NP_006051.1
LOC124901631	XR_007060322.1	n.83-2169C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.716-981G>A		intron_variant		1	NM_006060.6	ENSP00000331614	A1
	ENST00000644669.1	n.290-2169C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114621 AN: 152058 Hom.: 43448 Cov.: 33

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.777

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

GnomAD4 genome AF: 0.754 AC: 114734 AN: 152178 Hom.: 43502 Cov.: 33 AF XY: 0.753 AC XY: 56016 AN XY: 74380

Gnomad4 AFR AF: 0.737

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.774

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.690

Gnomad4 FIN AF: 0.747

Gnomad4 NFE AF: 0.775

Gnomad4 OTH AF: 0.775

Alfa AF: 0.768 Hom.: 24034

Bravo AF: 0.760

Asia WGS AF: 0.623 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.81
DANN	Benign	0.56

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: rs6954833; hg19: chr7-50458446;