rs79972275

Positions:

• chr19-18073507-G-A

Variant summary

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

The NM_005535.3(IL12RB1):​c.783+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00913 in 1,573,350 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (107 hom.)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.526

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-18073507-G-A is Benign according to our data. Variant chr19-18073507-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18073507-G-A is described in Lovd as [Likely_benign]. Variant chr19-18073507-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00564 (858/152024) while in subpopulation SAS AF= 0.0106 (51/4810). AF 95% confidence interval is 0.00871. There are 7 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.783+10C>T		intron_variant		ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.783+10C>T		intron_variant		1	NM_005535.3	P1
IL12RB1	ENST00000322153.11	c.783+10C>T		intron_variant		1
IL12RB1	ENST00000600835.6	c.783+10C>T		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 859 AN: 151906 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00165

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00932

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00648 AC: 1624 AN: 250570 Hom.: 11 AF XY: 0.00695 AC XY: 942 AN XY: 135576

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.000834

Gnomad NFE exome AF: 0.00890

Gnomad OTH exome AF: 0.00900

GnomAD4 exome AF: 0.00950 AC: 13507 AN: 1421326 Hom.: 107 Cov.: 28 AF XY: 0.00966 AC XY: 6850 AN XY: 709278

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00955

GnomAD4 genome AF: 0.00564 AC: 858 AN: 152024 Hom.: 7 Cov.: 31 AF XY: 0.00509 AC XY: 378 AN XY: 74310

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00387

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.000945

Gnomad4 NFE AF: 0.00931

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00587 Hom.: 2

Bravo AF: 0.00571

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Immunodeficiency 27A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

IL12RB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79972275; hg19: chr19-18184317;