chr7-50327679-G-A

Position:

chr7-50327679-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The NM_006060.6(IKZF1):c.82G>A(p.Asp28Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,396 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

IKZF1
NM_006060.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.92

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 -5 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=0.3284362).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000144 (21/1461246) while in subpopulation AMR AF= 0.000179 (8/44682). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF1	NM_006060.6 linkuse as main transcript	c.82G>A	p.Asp28Asn	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.82G>A	p.Asp28Asn	missense_variant	3/8	1	NM_006060.6	ENSP00000331614	A1	Q13422-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000242

AC:

AN:

247638

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461246

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.0000227

ExAC

AF:

0.0000249

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

Dec 06, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 28 of the IKZF1 protein (p.Asp28Asn). This variant is present in population databases (rs778910457, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1975171). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

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

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.061

MetaRNN

Benign

0.33

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

MetaSVM

Benign

-1.2

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.21

Sift

Uncertain

0.0030

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

Sift4G

Benign

0.15

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

Polyphen

1.0, 0.98, 1.0

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

Vest4

0.29, 0.37, 0.35, 0.31, 0.31, 0.38, 0.38, 0.31, 0.38

MutPred

0.23

Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);Gain of glycosylation at T23 (P = 0.1837);.;

MVP

0.44

MPC

2.0

ClinPred

0.85

GERP RS

5.7

Varity_R

0.22

gMVP

0.071

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