19-18059574-G-A

Variant names:

• chr19-18059574-G-A
• rs3746190
• NM_005535.3:c.*34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.*34C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 778,530 control chromosomes in the GnomAD database, including 45,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7318 hom., cov: 32)
  • Exomes 𝑓: 0.34 (38563 hom.)
• Consequence: IL12RB1 NM_005535.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00200
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-18059574-G-A is Benign according to our data. Variant chr19-18059574-G-A is described in ClinVar as Benign. ClinVar VariationId is 328572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.*34C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.*34C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.*34C>T		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42868 AN: 151944 Hom.: 7318 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.302 AC: 73419 AN: 243418 AF XY: 0.308

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.338 AC: 211489 AN: 626468 Hom.: 38563 Cov.: 0 AF XY: 0.336 AC XY: 114603 AN XY: 341138

African (AFR) AF: 0.103 AC: 1813 AN: 17684

American (AMR) AF: 0.193 AC: 8362 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 7107 AN: 20928

East Asian (EAS) AF: 0.190 AC: 6859 AN: 36030

South Asian (SAS) AF: 0.231 AC: 16064 AN: 69498

European-Finnish (FIN) AF: 0.451 AC: 23916 AN: 52984

Middle Eastern (MID) AF: 0.350 AC: 1451 AN: 4140

European-Non Finnish (NFE) AF: 0.387 AC: 134903 AN: 348840

Other (OTH) AF: 0.334 AC: 11014 AN: 33000

GnomAD4 genome AF: 0.282 AC: 42867 AN: 152062 Hom.: 7318 Cov.: 32 AF XY: 0.284 AC XY: 21085 AN XY: 74308

African (AFR) AF: 0.105 AC: 4363 AN: 41488

American (AMR) AF: 0.221 AC: 3381 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1191 AN: 3464

East Asian (EAS) AF: 0.135 AC: 699 AN: 5166

South Asian (SAS) AF: 0.230 AC: 1110 AN: 4822

European-Finnish (FIN) AF: 0.470 AC: 4971 AN: 10570

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26286 AN: 67966

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.326 Hom.: 3259

Bravo AF: 0.255

Asia WGS AF: 0.169 AC: 593 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.59
PhyloP100		-0.0020
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3746190; hg19: chr19-18170384; COSMIC: COSV74045533;