7-50327622-T-A

Variant names:

• chr7-50327622-T-A
• rs754363805
• NM_006060.6:c.41-16T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_006060.6(IKZF1):​c.41-16T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IKZF1 NM_006060.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.628
• Publications: 0 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: Illumina, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autoimmune disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-50327622-T-A is Benign according to our data. Variant chr7-50327622-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2041852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000276 (4/1450582) while in subpopulation AFR AF = 0.0000908 (3/33034). AF 95% confidence interval is 0.0000241. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	NM_006060.6	MANE Select	c.41-16T>A		intron	N/A	NP_006051.1	Q13422-1
	IKZF1	NM_001410879.1		c.41-16T>A		intron	N/A	NP_001397808.1	A0A8V8TNQ0
	IKZF1	NM_001220765.3		c.41-16T>A		intron	N/A	NP_001207694.1	Q13422-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	ENST00000331340.8	TSL:1 MANE Select	c.41-16T>A		intron	N/A	ENSP00000331614.3	Q13422-1
	IKZF1	ENST00000359197.9	TSL:1	c.41-16T>A		intron	N/A	ENSP00000352123.5	Q13422-7
	IKZF1	ENST00000439701.2	TSL:1	c.41-16T>A		intron	N/A	ENSP00000413025.1	Q13422-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000427 AC: 1 AN: 234102 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450582 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720538

African (AFR) AF: 0.0000908 AC: 3 AN: 33034

American (AMR) AF: 0.0000231 AC: 1 AN: 43260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.00 AC: 0 AN: 84244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106532

Other (OTH) AF: 0.00 AC: 0 AN: 59900

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.66
PhyloP100		-0.63
PromoterAI		-0.032	Neutral
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: rs754363805; hg19: chr7-50367218;