chr7-50402361-G-A

Variant names:

• chr7-50402361-G-A
• rs11552046
• NM_006060.6:c.*1734G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006060.6(IKZF1):​c.*1734G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 230,132 control chromosomes in the GnomAD database, including 68 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 0.014 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (3 hom.)
• Consequence: IKZF1 NM_006060.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 2 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).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2180/152182) while in subpopulation AFR AF = 0.0506 (2098/41492). AF 95% confidence interval is 0.0488. There are 65 homozygotes in GnomAd4. There are 1046 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2180 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006060.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	NM_006060.6	MANE Select	c.*1734G>A		3_prime_UTR	Exon 8 of 8	NP_006051.1
	IKZF1	NM_001410879.1		c.*1734G>A		3_prime_UTR	Exon 9 of 9	NP_001397808.1
	IKZF1	NM_001220765.3		c.*1734G>A		3_prime_UTR	Exon 7 of 7	NP_001207694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	ENST00000331340.8	TSL:1 MANE Select	c.*1734G>A		3_prime_UTR	Exon 8 of 8	ENSP00000331614.3
	IKZF1	ENST00000359197.9	TSL:1	c.*1734G>A		3_prime_UTR	Exon 7 of 7	ENSP00000352123.5
	IKZF1	ENST00000439701.2	TSL:1	c.*1734G>A		3_prime_UTR	Exon 7 of 7	ENSP00000413025.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2174 AN: 152064 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00277 AC: 216 AN: 77950 Hom.: 3 Cov.: 0 AF XY: 0.00223 AC XY: 80 AN XY: 35940

African (AFR) AF: 0.0449 AC: 167 AN: 3718

American (AMR) AF: 0.00501 AC: 12 AN: 2396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4948

East Asian (EAS) AF: 0.00 AC: 0 AN: 11140

South Asian (SAS) AF: 0.00 AC: 0 AN: 680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.00213 AC: 1 AN: 470

European-Non Finnish (NFE) AF: 0.0000625 AC: 3 AN: 48010

Other (OTH) AF: 0.00505 AC: 33 AN: 6530

GnomAD4 genome AF: 0.0143 AC: 2180 AN: 152182 Hom.: 65 Cov.: 33 AF XY: 0.0141 AC XY: 1046 AN XY: 74422

African (AFR) AF: 0.0506 AC: 2098 AN: 41492

American (AMR) AF: 0.00419 AC: 64 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00675 Hom.: 10

Bravo AF: 0.0162

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.1
DANN	Benign	0.52
PhyloP100		-0.026

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: rs11552046; hg19: chr7-50470059;