19-18059578-G-A

Variant names:

• chr19-18059578-G-A
• rs188415514
• NM_005535.3:c.*30C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005535.3(IL12RB1):​c.*30C>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 0.0014 in 780,064 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: IL12RB1 NM_005535.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.20

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00111 (169/152278) while in subpopulation NFE AF= 0.0016 (109/68038). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.*30C>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	c.*30C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835	c.*30C>T		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00119 AC: 293 AN: 245352 Hom.: 0 AF XY: 0.00127 AC XY: 169 AN XY: 133298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.00147 AC: 923 AN: 627786 Hom.: 2 Cov.: 0 AF XY: 0.00155 AC XY: 530 AN XY: 341920

Gnomad4 AFR exome AF: 0.0000565

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.000621

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00173

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.000835

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.058
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs188415514; hg19: chr19-18170388;