rs11575935

Variant names:

• chr19-18063921-C-T
• rs11575935
• NM_005535.3:c.1573G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A525A) has been classified 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:8
• Conservation: PhyloP100: 0.439
• Publications: 22 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=0.0067195).
• BP6: Variant 19-18063921-C-T is Benign according to our data. Variant chr19-18063921-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.1573G>A	p.Ala525Thr	missense	Exon 13 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.1693G>A	p.Ala565Thr	missense	Exon 14 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1594G>A	p.Ala532Thr	missense	Exon 13 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.1573G>A	p.Ala525Thr	missense	Exon 13 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1573G>A	p.Ala525Thr	missense	Exon 14 of 18	ENSP00000470788.1	P42701-1

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

GnomAD2 exomes AF: 0.0111 AC: 2755 AN: 248232 AF XY: 0.0123

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 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

African (AFR) AF: 0.00938 AC: 314 AN: 33474

American (AMR) AF: 0.00172 AC: 77 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 345 AN: 26114

East Asian (EAS) AF: 0.0398 AC: 1581 AN: 39694

South Asian (SAS) AF: 0.0401 AC: 3459 AN: 86204

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53332

Middle Eastern (MID) AF: 0.0174 AC: 100 AN: 5760

European-Non Finnish (NFE) AF: 0.000872 AC: 969 AN: 1111608

Other (OTH) AF: 0.00910 AC: 549 AN: 60330

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

African (AFR) AF: 0.00898 AC: 373 AN: 41534

American (AMR) AF: 0.00229 AC: 35 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.0454 AC: 234 AN: 5156

South Asian (SAS) AF: 0.0409 AC: 197 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00540 Hom.: 35

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.44
PrimateAI	Benign	0.37	T
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.064
MPC		0.21
ClinPred		0.0087	T
GERP RS		2.1
Varity_R		0.049
gMVP		0.28
Mutation Taster		=81/19	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: rs11575935; hg19: chr19-18174731;