NM_005535.3:c.-111A>T

Variant names:

• chr19-18086934-T-A
• rs393548
• NM_005535.3:c.-111A>T

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.-111A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,547,552 control chromosomes in the GnomAD database, including 34,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3496 hom., cov: 31)
  • Exomes 𝑓: 0.21 (31230 hom.)
• Consequence: IL12RB1 NM_005535.3 5_prime_UTR
• Scores: Splicing: ADA: 0.00006553
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.34
• Publications: 28 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 (BayesDel_noAF=-0.85).
• BP6: Variant 19-18086934-T-A is Benign according to our data. Variant chr19-18086934-T-A is described in ClinVar as Benign. ClinVar VariationId is 402972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 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.-111A>T		5_prime_UTR	Exon 1 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001440424.1		c.-111A>T		5_prime_UTR	Exon 1 of 17	NP_001427353.1
	IL12RB1	NM_001440425.1		c.-111A>T		5_prime_UTR	Exon 1 of 17	NP_001427354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.-111A>T		5_prime_UTR	Exon 1 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.-109-2A>T		splice_acceptor intron	N/A	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000430026.7	TSL:4	c.-111A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000403103.3	X6RGM1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32143 AN: 151432 Hom.: 3487 Cov.: 31

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.193 AC: 29266 AN: 151862 AF XY: 0.195

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.209 AC: 291921 AN: 1396002 Hom.: 31230 Cov.: 32 AF XY: 0.209 AC XY: 143993 AN XY: 689156

African (AFR) AF: 0.247 AC: 7727 AN: 31248

American (AMR) AF: 0.136 AC: 4784 AN: 35208

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5099 AN: 25070

East Asian (EAS) AF: 0.193 AC: 6931 AN: 35846

South Asian (SAS) AF: 0.192 AC: 15243 AN: 79506

European-Finnish (FIN) AF: 0.217 AC: 10269 AN: 47288

Middle Eastern (MID) AF: 0.191 AC: 1084 AN: 5682

European-Non Finnish (NFE) AF: 0.212 AC: 228993 AN: 1078274

Other (OTH) AF: 0.204 AC: 11791 AN: 57880

GnomAD4 genome AF: 0.212 AC: 32195 AN: 151550 Hom.: 3496 Cov.: 31 AF XY: 0.212 AC XY: 15731 AN XY: 74048

African (AFR) AF: 0.248 AC: 10214 AN: 41268

American (AMR) AF: 0.152 AC: 2322 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 692 AN: 3466

East Asian (EAS) AF: 0.154 AC: 798 AN: 5168

South Asian (SAS) AF: 0.191 AC: 921 AN: 4816

European-Finnish (FIN) AF: 0.229 AC: 2392 AN: 10430

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.210 AC: 14251 AN: 67858

Other (OTH) AF: 0.209 AC: 439 AN: 2098

Alfa AF: 0.215 Hom.: 680

Bravo AF: 0.203

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.54
PhyloP100		-1.3
PromoterAI		-0.074	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0060
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: rs393548; hg19: chr19-18197744; COSMIC: COSV59096451; COSMIC: COSV59096451;