NM_006060.6:c.7G>C

Variant names:

• chr7-50319068-G-C
• NM_006060.6:c.7G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006060.6(IKZF1):​c.7G>C​(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKZF1 NM_006060.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 autoimmune disease, pancytopenia due to IKZF1 mutations.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18398356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF1	NM_006060.6	c.7G>C	p.Ala3Pro	missense_variant	Exon 2 of 8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8	c.7G>C	p.Ala3Pro	missense_variant	Exon 2 of 8	1	NM_006060.6	ENSP00000331614.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;.;T;.;T;T;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;.;.;D;D;D;.;D;D;D;T;T;T;D;.;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.89	.;.;.;.;N;D;.;N;N;N;N;N;N;.;N;N;.
REVEL	Benign	0.088
Sift	Uncertain	0.022	.;.;.;.;D;D;.;D;D;T;D;D;D;.;D;T;.
Sift4G	Benign	0.077	.;.;.;.;T;D;T;T;T;T;T;T;D;D;T;T;.
Polyphen		0.052, 1.0, 0.21, 0.73	.;.;B;.;B;D;.;B;.;P;.;.;.;.;B;P;.
Vest4		0.13, 0.26, 0.20, 0.14, 0.14, 0.21, 0.23, 0.086, 0.16, 0.14, 0.14
MutPred		0.23		Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);Loss of stability (P = 0.0585);
MVP		0.34
MPC		1.2
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.27

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: chr7-50358664;