NM_006060.6:c.*1831G>C

Variant names:

• chr7-50402458-G-C
• rs62447208
• NM_006060.6:c.*1831G>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.*1831G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 231,248 control chromosomes in the GnomAD database, including 3,445 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 0.16 (2176 hom., cov: 32)
  • Exomes 𝑓: 0.16 (1269 hom.)
• Consequence: IKZF1 NM_006060.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.387
• 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=-0.84).
• 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.*1831G>C		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.*1831G>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24777 AN: 151946 Hom.: 2177 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.164 AC: 13014 AN: 79184 Hom.: 1269 Cov.: 0 AF XY: 0.166 AC XY: 6048 AN XY: 36470

African (AFR) AF: 0.121 AC: 460 AN: 3808

American (AMR) AF: 0.192 AC: 465 AN: 2426

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 890 AN: 4992

East Asian (EAS) AF: 0.0204 AC: 230 AN: 11274

South Asian (SAS) AF: 0.195 AC: 134 AN: 686

European-Finnish (FIN) AF: 0.182 AC: 12 AN: 66

Middle Eastern (MID) AF: 0.237 AC: 114 AN: 482

European-Non Finnish (NFE) AF: 0.196 AC: 9593 AN: 48842

Other (OTH) AF: 0.169 AC: 1116 AN: 6608

GnomAD4 genome AF: 0.163 AC: 24793 AN: 152064 Hom.: 2176 Cov.: 32 AF XY: 0.162 AC XY: 12075 AN XY: 74328

African (AFR) AF: 0.113 AC: 4694 AN: 41466

American (AMR) AF: 0.191 AC: 2926 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 585 AN: 3464

East Asian (EAS) AF: 0.0378 AC: 195 AN: 5158

South Asian (SAS) AF: 0.195 AC: 940 AN: 4810

European-Finnish (FIN) AF: 0.150 AC: 1583 AN: 10584

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

European-Non Finnish (NFE) AF: 0.194 AC: 13163 AN: 67976

Other (OTH) AF: 0.185 AC: 391 AN: 2116

Alfa AF: 0.181 Hom.: 303

Bravo AF: 0.164

Asia WGS AF: 0.112 AC: 390 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.39
PhyloP100		0.39
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: rs62447208; hg19: chr7-50470156;