rs1131690788

Positions:

• chr7-50382702-A-C
• chr7-50382702-A-G
• chr7-50382702-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_006060.6(IKZF1):​c.584A>C​(p.His195Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H195R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a region_of_interest Required for both high-affinity DNA binding and pericentromeric heterochromatin localization (size 15) in uniprot entity IKZF1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006060.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-50382702-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428611.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKZF1. . Gene score misZ 3.3753 (greater than the threshold 3.09). Trascript score misZ 3.423 (greater than threshold 3.09). GenCC has associacion of gene with autoimmune disease, pancytopenia due to IKZF1 mutations.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKZF1	NM_006060.6	c.584A>C	p.His195Pro	missense_variant	5/8	ENST00000331340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKZF1	ENST00000331340.8	c.584A>C	p.His195Pro	missense_variant	5/8	1	NM_006060.6	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;.;D;D;D;.
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.1	.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;.;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;.;D;D
Vest4		0.95, 0.93, 0.95, 0.96, 0.93, 0.95
MutPred		0.88		.;Loss of MoRF binding (P = 0.0676);Loss of MoRF binding (P = 0.0676);Loss of MoRF binding (P = 0.0676);.;Loss of MoRF binding (P = 0.0676);Loss of MoRF binding (P = 0.0676);.;
MVP		0.90
MPC		2.6
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.95
gMVP		0.96

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-50450400;