rs11575935

Positions:

• chr19-18063921-C-T

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.1573G>A​(p.Ala525Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0052 in 1,613,430 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (19 hom., cov: 30)
  • Exomes 𝑓: 0.0051 (148 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.439

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 (MetaRNN=0.0067195).
• BP6: Variant 19-18063921-C-T is Benign according to our data. Variant chr19-18063921-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18063921-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00652 (992/152208) while in subpopulation EAS AF= 0.0454 (234/5156). AF 95% confidence interval is 0.0406. There are 19 homozygotes in gnomad4. There are 537 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1573G>A	p.Ala525Thr	missense_variant	13/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1573G>A	p.Ala525Thr	missense_variant	13/17	1	NM_005535.3	ENSP00000472165	P1
IL12RB1	ENST00000600835.6	c.1573G>A	p.Ala525Thr	missense_variant	14/18	1		ENSP00000470788	P1

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 983 AN: 152090 Hom.: 18 Cov.: 30

Gnomad AFR AF: 0.00891

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0111 AC: 2755 AN: 248232 Hom.: 62 AF XY: 0.0123 AC XY: 1658 AN XY: 134770

Gnomad AFR exome AF: 0.00937

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0532

Gnomad SAS exome AF: 0.0398

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00506 AC: 7397 AN: 1461222 Hom.: 148 Cov.: 31 AF XY: 0.00621 AC XY: 4512 AN XY: 726904

Gnomad4 AFR exome AF: 0.00938

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.0401

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000872

Gnomad4 OTH exome AF: 0.00910

GnomAD4 genome AF: 0.00652 AC: 992 AN: 152208 Hom.: 19 Cov.: 30 AF XY: 0.00722 AC XY: 537 AN XY: 74400

Gnomad4 AFR AF: 0.00898

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.0454

Gnomad4 SAS AF: 0.0409

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00496 Hom.: 22

Bravo AF: 0.00655

ESP6500AA AF: 0.00937 AC: 39

ESP6500EA AF: 0.00142 AC: 12

ExAC AF: 0.0113 AC: 1362

Asia WGS AF: 0.0650 AC: 226 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 31367980) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 22, 2015	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.76	.;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.064
MPC		0.21
ClinPred		0.0087	T
GERP RS		2.1
Varity_R		0.049
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs11575935; hg19: chr19-18174731;