11-126292967-C-T

Variant names:

• chr11-126292967-C-T
• rs7932766
• NM_001318777.2:c.558C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001318777.2(TIRAP):​c.558C>T​(p.Ala186Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,986 control chromosomes in the GnomAD database, including 41,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2928 hom., cov: 33)
  • Exomes 𝑓: 0.22 (38757 hom.)
• Consequence: TIRAP NM_001318777.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.357
• Publications: 51 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-126292967-C-T is Benign according to our data. Variant chr11-126292967-C-T is described in ClinVar as Benign. ClinVar VariationId is 2688488.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.357 with no splicing effect.
• 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.558C>T	p.Ala186Ala	synonymous_variant	Exon 4 of 5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.558C>T	p.Ala186Ala	synonymous_variant	Exon 4 of 4		NP_001305705.1
TIRAP	NM_148910.3	c.558C>T	p.Ala186Ala	synonymous_variant	Exon 5 of 5		NP_683708.1
TIRAP	NM_001039661.2	c.558C>T	p.Ala186Ala	synonymous_variant	Exon 5 of 6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.558C>T	p.Ala186Ala	synonymous_variant	Exon 4 of 5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28420 AN: 152108 Hom.: 2925 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.178 AC: 44631 AN: 250232 AF XY: 0.183

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0952

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0289

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.223 AC: 325954 AN: 1461760 Hom.: 38757 Cov.: 41 AF XY: 0.222 AC XY: 161407 AN XY: 727166

African (AFR) AF: 0.127 AC: 4258 AN: 33480

American (AMR) AF: 0.101 AC: 4508 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4723 AN: 26134

East Asian (EAS) AF: 0.0353 AC: 1400 AN: 39700

South Asian (SAS) AF: 0.156 AC: 13444 AN: 86250

European-Finnish (FIN) AF: 0.190 AC: 10170 AN: 53388

Middle Eastern (MID) AF: 0.127 AC: 732 AN: 5768

European-Non Finnish (NFE) AF: 0.247 AC: 274238 AN: 1111930

Other (OTH) AF: 0.207 AC: 12481 AN: 60392

GnomAD4 genome AF: 0.187 AC: 28436 AN: 152226 Hom.: 2928 Cov.: 33 AF XY: 0.180 AC XY: 13397 AN XY: 74414

African (AFR) AF: 0.131 AC: 5435 AN: 41540

American (AMR) AF: 0.137 AC: 2093 AN: 15300

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

East Asian (EAS) AF: 0.0333 AC: 173 AN: 5190

South Asian (SAS) AF: 0.155 AC: 748 AN: 4828

European-Finnish (FIN) AF: 0.191 AC: 2026 AN: 10602

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16703 AN: 67982

Other (OTH) AF: 0.194 AC: 408 AN: 2108

Alfa AF: 0.219 Hom.: 6074

Bravo AF: 0.180

Asia WGS AF: 0.0940 AC: 330 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	-0.48
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		-0.36
Mutation Taster		=100/0	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: rs7932766; hg19: chr11-126162862; COSMIC: COSV67024244; COSMIC: COSV67024244;