chr1-67168129-G-T

Position:

• chr1-67168129-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144701.3(IL23R):​c.9G>T​(p.Gln3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 1,602,556 control chromosomes in the GnomAD database, including 228,378 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.52 (20363 hom., cov: 32)
  • Exomes 𝑓: 0.53 (208015 hom.)
• Consequence: IL23R NM_144701.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.735

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1682439E-5).
• BP6: Variant 1-67168129-G-T is Benign according to our data. Variant chr1-67168129-G-T is described in ClinVar as [Benign]. Clinvar id is 1169496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL23R	NM_144701.3	c.9G>T	p.Gln3His	missense_variant	2/11	ENST00000347310.10
IL23R	XM_011540790.4	c.9G>T	p.Gln3His	missense_variant	2/11
IL23R	XM_011540791.4	c.9G>T	p.Gln3His	missense_variant	2/11
IL23R	XM_047447227.1	c.9G>T	p.Gln3His	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL23R	ENST00000347310.10	c.9G>T	p.Gln3His	missense_variant	2/11	1	NM_144701.3	P1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78178 AN: 151714 Hom.: 20359 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.478

GnomAD3 exomes AF: 0.524 AC: 131693 AN: 251106 Hom.: 35542 AF XY: 0.535 AC XY: 72635 AN XY: 135720

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.596

Gnomad EAS exome AF: 0.644

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.532

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.532 AC: 772277 AN: 1450724 Hom.: 208015 Cov.: 31 AF XY: 0.536 AC XY: 387377 AN XY: 722404

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.590

Gnomad4 EAS exome AF: 0.616

Gnomad4 SAS exome AF: 0.629

Gnomad4 FIN exome AF: 0.496

Gnomad4 NFE exome AF: 0.531

Gnomad4 OTH exome AF: 0.529

GnomAD4 genome AF: 0.515 AC: 78200 AN: 151832 Hom.: 20363 Cov.: 32 AF XY: 0.515 AC XY: 38211 AN XY: 74188

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.610

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.512

Gnomad4 NFE AF: 0.528

Gnomad4 OTH AF: 0.477

Alfa AF: 0.528 Hom.: 52815

Bravo AF: 0.504

TwinsUK AF: 0.537 AC: 1993

ALSPAC AF: 0.516 AC: 1988

ESP6500AA AF: 0.500 AC: 2203

ESP6500EA AF: 0.528 AC: 4540

ExAC AF: 0.528 AC: 64158

Asia WGS AF: 0.563 AC: 1959 AN: 3474

EpiCase AF: 0.529

EpiControl AF: 0.525

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 57% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.13
Sift	Benign	0.38	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.16		Loss of sheet (P = 0.1158);
MPC		0.60
ClinPred		0.0054	T
GERP RS		2.0
Varity_R		0.036
gMVP		0.56

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

Other links and lift over

dbSNP: rs1884444; hg19: chr1-67633812; COSMIC: COSV61376571;