1-67168179-G-T

Position:

• chr1-67168179-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144701.3(IL23R):​c.59G>T​(p.Trp20Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000206 in 1,455,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: IL23R NM_144701.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

Genes affected

IL23R (HGNC:19100): (interleukin 23 receptor) The protein encoded by this gene is a subunit of the receptor for IL23A/IL23. This protein pairs with the receptor molecule IL12RB1/IL12Rbeta1, and both are required for IL23A signaling. This protein associates constitutively with Janus kinase 2 (JAK2), and also binds to transcription activator STAT3 in a ligand-dependent manner. [provided by RefSeq, Jul 2008]

C1orf141 (HGNC:32044): (chromosome 1 open reading frame 141)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL23R	NM_144701.3	c.59G>T	p.Trp20Leu	missense_variant	2/11	ENST00000347310.10	NP_653302.2
IL23R	XM_011540790.4	c.59G>T	p.Trp20Leu	missense_variant	2/11		XP_011539092.1
IL23R	XM_011540791.4	c.59G>T	p.Trp20Leu	missense_variant	2/11		XP_011539093.1
IL23R	XM_047447227.1	c.59G>T	p.Trp20Leu	missense_variant	2/11		XP_047303183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL23R	ENST00000347310.10	c.59G>T	p.Trp20Leu	missense_variant	2/11	1	NM_144701.3	ENSP00000321345	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1455284 Hom.: 0 Cov.: 29 AF XY: 0.0000207 AC XY: 15 AN XY: 724430

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: 0.0000253

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This variant has not been reported in the literature in individuals affected with IL23R-related conditions. ClinVar contains an entry for this variant (Variation ID: 1917576). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 20 of the IL23R protein (p.Trp20Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.84	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.64
Sift	Benign	0.074	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.60
MutPred		0.62		Loss of sheet (P = 0.0037);
MVP		0.94
MPC		0.79
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.17
gMVP		0.54

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

Other links and lift over

dbSNP: rs765086515; hg19: chr1-67633862;