chr7-50327676-G-A

Position:

chr7-50327676-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_006060.6(IKZF1):c.79G>A(p.Gly27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,366 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 1 hom. )

Consequence

IKZF1
NM_006060.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.587

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 Benign. Variant got -7 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=0.05621922).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF1	NM_006060.6 linkuse as main transcript	c.79G>A	p.Gly27Ser	missense_variant	3/8	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.79G>A	p.Gly27Ser	missense_variant	3/8	1	NM_006060.6	ENSP00000331614	A1	Q13422-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

247776

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000985

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2023

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 (rs749271573, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the IKZF1 protein (p.Gly27Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.0031

MetaRNN

Benign

0.056

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

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.31

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

REVEL

Benign

0.050

Sift

Benign

0.078

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

Sift4G

Benign

0.65

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

Polyphen

0.0010, 0.43

.;.;B;.;B;B;.;B;.;B;.;B;B;.;.

Vest4

0.13, 0.14, 0.12, 0.15, 0.13, 0.15, 0.14, 0.15

MutPred

0.45

Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);Gain of phosphorylation at G27 (P = 0.0027);.;

MVP

0.20

MPC

0.94

ClinPred

0.037

GERP RS

0.37

Varity_R

0.043

gMVP

0.057

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