rs41313262

Positions:

• chr1-67240217-G-A
• chr1-67240217-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000347310.10(IL23R):​c.1084G>A​(p.Val362Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,612,506 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 33)
  • Exomes 𝑓: 0.013 (157 hom.)
• Consequence: IL23R ENST00000347310.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.808

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030460954).
• BP6: Variant 1-67240217-G-A is Benign according to our data. Variant chr1-67240217-G-A is described in ClinVar as [Benign]. Clinvar id is 1165955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67240217-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.01 (1524/152200) while in subpopulation AMR AF= 0.0171 (261/15288). AF 95% confidence interval is 0.0154. There are 14 homozygotes in gnomad4. There are 695 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL23R	NM_144701.3	c.1084G>A	p.Val362Ile	missense_variant	9/11	ENST00000347310.10	NP_653302.2
IL23R	XM_011540790.4	c.1084G>A	p.Val362Ile	missense_variant	9/11		XP_011539092.1
IL23R	XM_011540791.4	c.1084G>A	p.Val362Ile	missense_variant	9/11		XP_011539093.1
IL23R	XM_047447227.1	c.1084G>A	p.Val362Ile	missense_variant	9/11		XP_047303183.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL23R	ENST00000347310.10	c.1084G>A	p.Val362Ile	missense_variant	9/11	1	NM_144701.3	ENSP00000321345	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1525 AN: 152082 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0111 AC: 2778 AN: 251222 Hom.: 28 AF XY: 0.0116 AC XY: 1572 AN XY: 135796

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00487

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0127 AC: 18492 AN: 1460306 Hom.: 157 Cov.: 29 AF XY: 0.0125 AC XY: 9080 AN XY: 726596

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00479

Gnomad4 FIN exome AF: 0.00261

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0100 AC: 1524 AN: 152200 Hom.: 14 Cov.: 33 AF XY: 0.00934 AC XY: 695 AN XY: 74414

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00180

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0147 Hom.: 33

Bravo AF: 0.0119

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0117 AC: 1415

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0174

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	IL23R: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.17
DANN	Benign	0.77
DEOGEN2	Benign	0.061	.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.26	T;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.060	.;N;.
REVEL	Benign	0.022
Sift	Benign	0.30	.;T;.
Sift4G	Benign	0.30	.;T;T
Polyphen		0.0010, 0.0060	.;B;B
Vest4		0.14, 0.015
MPC		0.13
ClinPred		0.0026	T
GERP RS		-6.2
Varity_R		0.033
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41313262; hg19: chr1-67705900; COSMIC: COSV61373104;