rs383483

Variant names:

• chr19-18061076-A-G
• rs383483
• NM_005535.3:c.1791+46T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005535.3(IL12RB1):​c.1791+46T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 968,378 control chromosomes in the GnomAD database, including 116,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (18647 hom., cov: 31)
  • Exomes 𝑓: 0.48 (97493 hom.)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.246
• Publications: 20 publications found

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]

IL12RB1 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 19-18061076-A-G is Benign according to our data. Variant chr19-18061076-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688394.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1791+46T>C		intron_variant	Intron 15 of 16	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1791+46T>C		intron_variant	Intron 15 of 16	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1791+46T>C		intron_variant	Intron 16 of 17	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74540 AN: 151888 Hom.: 18621 Cov.: 31

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.452 AC: 83826 AN: 185586 AF XY: 0.452

Gnomad AFR exome AF: 0.523

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.373

Gnomad FIN exome AF: 0.561

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.468

GnomAD4 exome AF: 0.483 AC: 394020 AN: 816372 Hom.: 97493 Cov.: 11 AF XY: 0.478 AC XY: 203847 AN XY: 426374

African (AFR) AF: 0.517 AC: 10754 AN: 20802

American (AMR) AF: 0.310 AC: 11407 AN: 36784

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 10468 AN: 21676

East Asian (EAS) AF: 0.405 AC: 14123 AN: 34844

South Asian (SAS) AF: 0.333 AC: 22784 AN: 68478

European-Finnish (FIN) AF: 0.558 AC: 28195 AN: 50550

Middle Eastern (MID) AF: 0.492 AC: 2257 AN: 4592

European-Non Finnish (NFE) AF: 0.510 AC: 275162 AN: 539680

Other (OTH) AF: 0.484 AC: 18870 AN: 38966

GnomAD4 genome AF: 0.491 AC: 74594 AN: 152006 Hom.: 18647 Cov.: 31 AF XY: 0.489 AC XY: 36339 AN XY: 74274

African (AFR) AF: 0.517 AC: 21442 AN: 41464

American (AMR) AF: 0.371 AC: 5672 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1665 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1994 AN: 5156

South Asian (SAS) AF: 0.337 AC: 1621 AN: 4816

European-Finnish (FIN) AF: 0.576 AC: 6086 AN: 10558

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34595 AN: 67958

Other (OTH) AF: 0.475 AC: 1003 AN: 2110

Alfa AF: 0.496 Hom.: 8833

Bravo AF: 0.477

Asia WGS AF: 0.402 AC: 1399 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		0.25
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs383483; hg19: chr19-18171886; COSMIC: COSV74045534;