11-126293717-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001318777.2(TIRAP):c.*30T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,612,412 control chromosomes in the GnomAD database, including 41,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2702 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38537 hom.)
• Consequence: TIRAP NM_001318777.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.909

Genes affected

TIRAP (HGNC:17192): (TIR domain containing adaptor protein) The innate immune system recognizes microbial pathogens through Toll-like receptors (TLRs), which identify pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns and all TLRs have a Toll-interleukin 1 receptor (TIR) domain, which is responsible for signal transduction. The protein encoded by this gene is a TIR adaptor protein involved in the TLR4 signaling pathway of the immune system. It activates NF-kappa-B, MAPK1, MAPK3 and JNK, which then results in cytokine secretion and the inflammatory response. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 11-126293717-T-G is Benign according to our data. Variant chr11-126293717-T-G is described in ClinVar as [Benign]. Clinvar id is 2688489.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.*30T>G		3_prime_UTR_variant	5/5	ENST00000392679.6
TIRAP	NM_001039661.2	c.*30T>G		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.*30T>G		3_prime_UTR_variant	5/5	2	NM_001318777.2	P1
	ENST00000533378.1	n.127+411A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26524 AN: 151966 Hom.: 2700 Cov.: 32

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.175 AC: 44010 AN: 251374 Hom.: 4618 AF XY: 0.180 AC XY: 24494 AN XY: 135860

Gnomad AFR exome AF: 0.0832

Gnomad AMR exome AF: 0.0927

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0290

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.222 AC: 323489 AN: 1460328 Hom.: 38537 Cov.: 32 AF XY: 0.221 AC XY: 160384 AN XY: 726550

Gnomad4 AFR exome AF: 0.0841

Gnomad4 AMR exome AF: 0.0975

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.0353

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.174 AC: 26534 AN: 152084 Hom.: 2702 Cov.: 32 AF XY: 0.168 AC XY: 12497 AN XY: 74328

Gnomad4 AFR AF: 0.0877

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.182

Alfa AF: 0.221 Hom.: 4288

Bravo AF: 0.165

Asia WGS AF: 0.0920 AC: 321 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	7.2
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs8177376; hg19: chr11-126163612; COSMIC: COSV67024678; COSMIC: COSV67024678;