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: Orphanet, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005535.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.1094T>C	p.Met365Thr	missense	Exon 10 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.1214T>C	p.Met405Thr	missense	Exon 11 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1115T>C	p.Met372Thr	missense	Exon 10 of 17	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.1094T>C	p.Met365Thr	missense	Exon 10 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1094T>C	p.Met365Thr	missense	Exon 11 of 18	ENSP00000470788.1	P42701-1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.95
PrimateAI	Benign	0.26	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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;