19-18076318-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_005535.3(IL12RB1):c.559G>A(p.Gly187Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,422,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G187G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.299

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Fibronectin type-III 2 (size 92) in uniprot entity I12R1_HUMAN there are 18 pathogenic changes around while only 2 benign (90%) in NM_005535.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3303283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.559G>A	p.Gly187Arg	missense_variant	6/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.559G>A	p.Gly187Arg	missense_variant	6/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.559G>A	p.Gly187Arg	missense_variant	7/18	1		P1
IL12RB1	ENST00000322153.11	c.559G>A	p.Gly187Arg	missense_variant	6/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251192 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 20 AN: 1270680 Hom.: 0 Cov.: 20 AF XY: 0.0000187 AC XY: 12 AN XY: 641980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000747

Gnomad4 OTH exome AF: 0.0000185

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74482

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

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

Bravo AF: 0.0000264

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.559G>A (p.G187R) alteration is located in exon 6 (coding exon 6) of the IL12RB1 gene. This alteration results from a G to A substitution at nucleotide position 559, causing the glycine (G) at amino acid position 187 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 187 of the IL12RB1 protein (p.Gly187Arg). This variant is present in population databases (rs564884307, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with IL12RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 639105). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	15
Dann	Benign	0.91
DEOGEN2	Benign	0.32	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.15	N
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.65	P;P;D
Vest4		0.44
MutPred		0.51		Loss of catalytic residue at G187 (P = 0.0679);Loss of catalytic residue at G187 (P = 0.0679);Loss of catalytic residue at G187 (P = 0.0679);
MVP		0.94
MPC		0.18
ClinPred		0.15	T
GERP RS		1.5
Varity_R		0.083
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs564884307; hg19: chr19-18187128;