chr7-50315611-G-C

Variant names:

• chr7-50315611-G-C
• rs6421315
• NM_006060.6:c.-14-3437G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006060.6(IKZF1):​c.-14-3437G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,086 control chromosomes in the GnomAD database, including 12,739 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 0.40 (12739 hom., cov: 33)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.653
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• pancytopenia due to IKZF1 mutations

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• autoimmune disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.-14-3437G>C		intron_variant	Intron 1 of 7	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.-14-3437G>C		intron_variant	Intron 1 of 7	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61371 AN: 151968 Hom.: 12727 Cov.: 33

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.404 AC: 61427 AN: 152086 Hom.: 12739 Cov.: 33 AF XY: 0.405 AC XY: 30131 AN XY: 74356

African (AFR) AF: 0.395 AC: 16384 AN: 41464

American (AMR) AF: 0.493 AC: 7531 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1161 AN: 3464

East Asian (EAS) AF: 0.597 AC: 3095 AN: 5184

South Asian (SAS) AF: 0.420 AC: 2024 AN: 4822

European-Finnish (FIN) AF: 0.358 AC: 3779 AN: 10568

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26165 AN: 67980

Other (OTH) AF: 0.401 AC: 846 AN: 2110

Alfa AF: 0.387 Hom.: 1409

Bravo AF: 0.412

Asia WGS AF: 0.550 AC: 1909 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	1.1
DANN	Benign	0.40
PhyloP100		-0.65

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: rs6421315; hg19: chr7-50355207;