rs778820674

Variant names:

• chr7-50391827-G-A
• rs778820674
• NM_006060.6:c.814G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP2 PP5 BP4 BS2

The NM_006060.6(IKZF1):​c.814G>A​(p.Ala272Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,552 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.88
• Publications: 5 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

ENSG00000285165 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the IKZF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.3753 (above the threshold of 3.09). Trascript score misZ: 3.423 (above the threshold of 3.09). GenCC associations: The gene is linked to pancytopenia due to IKZF1 mutations, autoimmune disease.
• PP5: Variant 7-50391827-G-A is Pathogenic according to our data. Variant chr7-50391827-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548705.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28837988). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF1	NM_006060.6	MANE Select	c.814G>A	p.Ala272Thr	missense	Exon 7 of 8	NP_006051.1	Q13422-1
	IKZF1	NM_001410879.1		c.874G>A	p.Ala292Thr	missense	Exon 8 of 9	NP_001397808.1	A0A8V8TNQ0
	IKZF1	NM_001220765.3		c.688G>A	p.Ala230Thr	missense	Exon 6 of 7	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.814G>A	p.Ala272Thr	missense	Exon 7 of 8	ENSP00000331614.3	Q13422-1
	IKZF1	ENST00000359197.9	TSL:1	c.688G>A	p.Ala230Thr	missense	Exon 6 of 7	ENSP00000352123.5	Q13422-7
	IKZF1	ENST00000439701.2	TSL:1	c.688G>A	p.Ala230Thr	missense	Exon 6 of 7	ENSP00000413025.1	Q13422-7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248700 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
1	-	-	Pancytopenia due to IKZF1 mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.82	T
PhyloP100		5.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.31	T
Sift4G	Benign	0.34	T
Polyphen		0.32	B
Vest4		0.33
MutPred		0.23		Gain of phosphorylation at A272 (P = 0.045)
MVP		0.40
MPC		0.94
ClinPred		0.90	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.19
gMVP		0.43
Mutation Taster		=59/41	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs778820674; hg19: chr7-50459525; COSMIC: COSV58781357;