rs375947

Variant names:

• chr19-18069641-A-G
• rs375947
• NM_005535.3:c.1094T>C

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.1094T>C​(p.Met365Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,612,186 control chromosomes in the GnomAD database, including 78,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M365I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (6814 hom., cov: 33)
  • Exomes 𝑓: 0.31 (71725 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.948
• Publications: 82 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 (MetaRNN=0.004220456).
• BP6: Variant 19-18069641-A-G is Benign according to our data. Variant chr19-18069641-A-G is described in ClinVar as Benign. ClinVar VariationId is 328588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1094T>C	p.Met365Thr	missense_variant	Exon 10 of 17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1094T>C	p.Met365Thr	missense_variant	Exon 10 of 17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1094T>C	p.Met365Thr	missense_variant	Exon 11 of 18	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44790 AN: 152018 Hom.: 6797 Cov.: 33

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.287 AC: 71468 AN: 248808 AF XY: 0.290

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.355

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.310 AC: 453258 AN: 1460050 Hom.: 71725 Cov.: 33 AF XY: 0.309 AC XY: 224601 AN XY: 726386

African (AFR) AF: 0.261 AC: 8745 AN: 33448

American (AMR) AF: 0.174 AC: 7788 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 8710 AN: 26134

East Asian (EAS) AF: 0.388 AC: 15387 AN: 39688

South Asian (SAS) AF: 0.231 AC: 19956 AN: 86236

European-Finnish (FIN) AF: 0.323 AC: 17099 AN: 52912

Middle Eastern (MID) AF: 0.303 AC: 1745 AN: 5766

European-Non Finnish (NFE) AF: 0.320 AC: 355188 AN: 1110814

Other (OTH) AF: 0.309 AC: 18640 AN: 60330

GnomAD4 genome AF: 0.295 AC: 44839 AN: 152136 Hom.: 6814 Cov.: 33 AF XY: 0.295 AC XY: 21934 AN XY: 74366

African (AFR) AF: 0.263 AC: 10916 AN: 41516

American (AMR) AF: 0.223 AC: 3411 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1131 AN: 3468

East Asian (EAS) AF: 0.372 AC: 1922 AN: 5170

South Asian (SAS) AF: 0.239 AC: 1155 AN: 4826

European-Finnish (FIN) AF: 0.337 AC: 3564 AN: 10574

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21813 AN: 67974

Other (OTH) AF: 0.295 AC: 624 AN: 2116

Alfa AF: 0.313 Hom.: 31102

Bravo AF: 0.284

TwinsUK AF: 0.312 AC: 1157

ALSPAC AF: 0.322 AC: 1242

ESP6500AA AF: 0.258 AC: 1071

ESP6500EA AF: 0.311 AC: 2613

ExAC AF: 0.289 AC: 34951

Asia WGS AF: 0.330 AC: 1149 AN: 3478

EpiCase AF: 0.322

EpiControl AF: 0.316

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:3

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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. -

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with tuberculosis susceptibility -

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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.017
DANN	Benign	0.26
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.19	.;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N;N
PhyloP100		-0.95
PrimateAI	Benign	0.26	T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.0060
MPC		0.097
ClinPred		0.0015	T
GERP RS		-4.5
Varity_R		0.042
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs375947; hg19: chr19-18180451; COSMIC: COSV59097336; COSMIC: COSV59097336;