rs62447207

Variant names:

• chr7-50402440-G-T
• rs62447207
• NM_006060.6:c.*1813G>T

Variant summary

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

The NM_006060.6(IKZF1):​c.*1813G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 231,050 control chromosomes in the GnomAD database, including 3,258 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 0.15 (2017 hom., cov: 33)
  • Exomes 𝑓: 0.16 (1241 hom.)
• Consequence: IKZF1 NM_006060.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 8 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.*1813G>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.*1813G>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22962 AN: 151984 Hom.: 2019 Cov.: 33

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.161 AC: 12745 AN: 78948 Hom.: 1241 Cov.: 0 AF XY: 0.164 AC XY: 5950 AN XY: 36328

African (AFR) AF: 0.0794 AC: 301 AN: 3790

American (AMR) AF: 0.186 AC: 448 AN: 2414

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 888 AN: 4978

East Asian (EAS) AF: 0.0204 AC: 229 AN: 11246

South Asian (SAS) AF: 0.194 AC: 132 AN: 680

European-Finnish (FIN) AF: 0.167 AC: 10 AN: 60

Middle Eastern (MID) AF: 0.243 AC: 115 AN: 474

European-Non Finnish (NFE) AF: 0.196 AC: 9531 AN: 48688

Other (OTH) AF: 0.165 AC: 1091 AN: 6618

GnomAD4 genome AF: 0.151 AC: 22968 AN: 152102 Hom.: 2017 Cov.: 33 AF XY: 0.151 AC XY: 11217 AN XY: 74354

African (AFR) AF: 0.0710 AC: 2945 AN: 41496

American (AMR) AF: 0.189 AC: 2889 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 586 AN: 3466

East Asian (EAS) AF: 0.0373 AC: 193 AN: 5170

South Asian (SAS) AF: 0.196 AC: 944 AN: 4820

European-Finnish (FIN) AF: 0.149 AC: 1581 AN: 10576

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13147 AN: 67970

Other (OTH) AF: 0.174 AC: 366 AN: 2108

Alfa AF: 0.171 Hom.: 293

Bravo AF: 0.150

Asia WGS AF: 0.110 AC: 382 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.58
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs62447207; hg19: chr7-50470138;