rs8177376

Variant names:

• chr11-126293717-T-G
• rs8177376
• ENST00000479770.2:n.*30T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The ENST00000479770.2(TIRAP):​n.*30T>G variant causes a non coding transcript exon 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 ENST00000479770.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.909
• Publications: 36 publications found

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]

ENSG00000254905 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.088).
• BP6: Variant 11-126293717-T-G is Benign according to our data. Variant chr11-126293717-T-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.*30T>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001039661.2	c.*30T>G		3_prime_UTR_variant	Exon 6 of 6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.*30T>G		3_prime_UTR_variant	Exon 5 of 5	2	NM_001318777.2	ENSP00000376446.1

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

GnomAD2 exomes AF: 0.175 AC: 44010 AN: 251374 AF XY: 0.180

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 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

African (AFR) AF: 0.0841 AC: 2814 AN: 33466

American (AMR) AF: 0.0975 AC: 4359 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4714 AN: 26114

East Asian (EAS) AF: 0.0353 AC: 1400 AN: 39698

South Asian (SAS) AF: 0.156 AC: 13448 AN: 86222

European-Finnish (FIN) AF: 0.190 AC: 10173 AN: 53404

Middle Eastern (MID) AF: 0.126 AC: 726 AN: 5768

European-Non Finnish (NFE) AF: 0.246 AC: 273574 AN: 1110602

Other (OTH) AF: 0.204 AC: 12281 AN: 60346

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

African (AFR) AF: 0.0877 AC: 3640 AN: 41486

American (AMR) AF: 0.132 AC: 2013 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3470

East Asian (EAS) AF: 0.0332 AC: 172 AN: 5176

South Asian (SAS) AF: 0.155 AC: 748 AN: 4824

European-Finnish (FIN) AF: 0.191 AC: 2021 AN: 10568

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16710 AN: 67972

Other (OTH) AF: 0.182 AC: 383 AN: 2110

Alfa AF: 0.213 Hom.: 5773

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8177376; hg19: chr11-126163612; COSMIC: COSV67024678; COSMIC: COSV67024678;