11-126293169-A-G

Position:

• chr11-126293169-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001318777.2(TIRAP):​c.646+114A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,566,470 control chromosomes in the GnomAD database, including 12,227 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1229 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10998 hom.)
• Consequence: TIRAP NM_001318777.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.544

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.646+114A>G		intron_variant		ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.*52A>G		3_prime_UTR_variant	4/4		NP_001305705.1
TIRAP	NM_148910.3	c.*52A>G		3_prime_UTR_variant	5/5		NP_683708.1
TIRAP	NM_001039661.2	c.646+114A>G		intron_variant			NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.646+114A>G		intron_variant		2	NM_001318777.2	ENSP00000376446	P1
	ENST00000533378.1	n.245T>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19009 AN: 152034 Hom.: 1227 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0816

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0892

GnomAD3 exomes AF: 0.121 AC: 24975 AN: 207238 Hom.: 1574 AF XY: 0.122 AC XY: 13883 AN XY: 113484

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0665

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.149

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.123 AC: 173874 AN: 1414318 Hom.: 10998 Cov.: 30 AF XY: 0.124 AC XY: 86662 AN XY: 700534

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.0684

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.135

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.125 AC: 19020 AN: 152152 Hom.: 1229 Cov.: 33 AF XY: 0.126 AC XY: 9389 AN XY: 74368

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0814

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.0949

Alfa AF: 0.116 Hom.: 1527

Bravo AF: 0.119

Asia WGS AF: 0.127 AC: 442 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.59
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs8177375; hg19: chr11-126163064; COSMIC: COSV67023985; COSMIC: COSV67023985;