chr7-50319087-T-C

Position:

chr7-50319087-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_006060.6(IKZF1):c.26T>C(p.Met9Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,656 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

IKZF1
NM_006060.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.94

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.19210106).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000046 (7/152204) while in subpopulation AMR AF= 0.000458 (7/15284). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF1	NM_006060.6 linkuse as main transcript	c.26T>C	p.Met9Thr	missense_variant	2/8	ENST00000331340.8	NP_006051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF1	ENST00000331340.8 linkuse as main transcript	c.26T>C	p.Met9Thr	missense_variant	2/8	1	NM_006060.6	ENSP00000331614	A1	Q13422-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248752

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000342

AC:

AN:

1461452

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acute lymphoid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Sep 23, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 9 of the IKZF1 protein (p.Met9Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

.;.;T;.;T;T;T;.;.;.;.;.;T;T;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;.;.;D;D;D;.;D;D;D;T;T;T;D;.;D

M_CAP

Benign

0.0068

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D;N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

.;.;.;.;N;D;.;N;N;N;N;N;N;.;N;N;.

REVEL

Benign

0.16

Sift

Uncertain

0.0020

.;.;.;.;D;D;.;D;D;D;D;D;D;.;D;D;.

Sift4G

Benign

0.37

.;.;.;.;T;D;D;T;T;T;T;T;T;T;T;T;.

Polyphen

0.094, 0.98, 0.33, 0.30

.;.;B;.;B;D;.;B;.;B;.;.;.;.;B;B;.

Vest4

0.51, 0.60, 0.52, 0.51, 0.53, 0.47, 0.52, 0.50, 0.49, 0.56, 0.51, 0.47

MutPred

0.26

Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);Gain of phosphorylation at M9 (P = 0.0227);

MVP

0.36

MPC

1.1

ClinPred

0.62

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over