Variant chr12-56340007-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016584.3(IL23A):c.473G>A(p.Arg158His) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,614,152 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

IL23A
NM_016584.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

Variant links:

Genes affected

IL23A (HGNC:15488): (interleukin 23 subunit alpha) This gene encodes a subunit of the heterodimeric cytokine interleukin 23 (IL23). IL23 is composed of this protein and the p40 subunit of interleukin 12 (IL12B). The receptor of IL23 is formed by the beta 1 subunit of IL12 (IL12RB1) and an IL23 specific subunit, IL23R. Both IL23 and IL12 can activate the transcription activator STAT4, and stimulate the production of interferon-gamma (IFNG). In contrast to IL12, which acts mainly on naive CD4(+) T cells, IL23 preferentially acts on memory CD4(+) T cells. [provided by RefSeq, Jul 2008]

IL23A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL23A	NM_016584.3 linkuse as main transcript	c.473G>A	p.Arg158His	missense_variant	4/4	ENST00000228534.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IL23A	ENST00000228534.6 linkuse as main transcript	c.473G>A	p.Arg158His	missense_variant	4/4	1	NM_016584.3	P1
IL23A	ENST00000619177.1 linkuse as main transcript	n.418G>A		non_coding_transcript_exon_variant	5/5	2
IL23A	ENST00000622119.4 linkuse as main transcript	n.411G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251342

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727234

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

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

Ambry Genetics

Nov 09, 2021

The c.473G>A (p.R158H) alteration is located in exon 4 (coding exon 4) of the IL23A gene. This alteration results from a G to A substitution at nucleotide position 473, causing the arginine (R) at amino acid position 158 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.28

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.51

MVP

0.59

MPC

0.83

ClinPred

0.67

GERP RS

5.1

Varity_R

0.68

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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