chr10-122994157-C-T

Position:

chr10-122994157-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001372123.1(IKZF5):c.883G>A(p.Ala295Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

IKZF5
NM_001372123.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.57

Variant links:

Genes affected

IKZF5 (HGNC:14283): (IKAROS family zinc finger 5) Members of the Ikaros (ZNFN1A1; MIM 603023) family of transcription factors, which includes Pegasus, are expressed in lymphocytes and are implicated in the control of lymphoid development.[supplied by OMIM, Jul 2002]

IKZF5 links:

PSTK (HGNC:28578): (phosphoseryl-tRNA kinase) Predicted to enable kinase activity and tRNA binding activity. Predicted to be involved in phosphorylation; selenocysteinyl-tRNA(Sec) biosynthetic process; and translation. Predicted to act upstream of or within selenocysteine incorporation. [provided by Alliance of Genome Resources, Apr 2022]

PSTK 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), IKZF5. . Gene score misZ 1.8899 (greater than the threshold 3.09). Trascript score misZ 3.2196 (greater than threshold 3.09). GenCC has associacion of gene with thrombocytopenia 7, autosomal thrombocytopenia with normal platelets.

BP4

Computational evidence support a benign effect (MetaRNN=0.08323017).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF5	NM_001372123.1 linkuse as main transcript	c.883G>A	p.Ala295Thr	missense_variant	5/5	ENST00000368886.10	NP_001359052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
IKZF5	ENST00000368886.10 linkuse as main transcript	c.883G>A	p.Ala295Thr	missense_variant	5/5	1	NM_001372123.1	ENSP00000357881	P1
IKZF5	ENST00000617859.4 linkuse as main transcript	c.883G>A	p.Ala295Thr	missense_variant	5/5	1		ENSP00000478056	P1
PSTK	ENST00000496079.1 linkuse as main transcript	n.586-486C>T		intron_variant, non_coding_transcript_variant		3
PSTK	ENST00000497219.5 linkuse as main transcript	n.1816-2962C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00000401

AC:

AN:

249538

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

Alfa

AF:

0.0000806

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 09, 2024

Variant summary: IKZF5 c.883G>A (p.Ala295Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249538 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.883G>A in individuals affected with Thrombocytopenia 7 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

T;T

Eigen

Benign

-0.10

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.75

T;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.64

N;.

REVEL

Benign

0.10

Sift

Benign

0.32

T;.

Sift4G

Benign

0.64

T;T

Polyphen

0.0010

B;B

Vest4

0.095

MVP

0.048

MPC

0.58

ClinPred

0.37

GERP RS

6.0

Varity_R

0.061

gMVP

0.33

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