11-126292712-G-A

Variant names:

• chr11-126292712-G-A
• rs3802814
• NM_001318777.2:c.303G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001318777.2(TIRAP):​c.303G>A​(p.Gln101Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,300 control chromosomes in the GnomAD database, including 16,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (1091 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15303 hom.)
• Consequence: TIRAP NM_001318777.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.04

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-126292712-G-A is Benign according to our data. Variant chr11-126292712-G-A is described in ClinVar as [Benign]. Clinvar id is 2688487.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.303G>A	p.Gln101Gln	synonymous_variant	Exon 4 of 5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.303G>A	p.Gln101Gln	synonymous_variant	Exon 4 of 4		NP_001305705.1
TIRAP	NM_148910.3	c.303G>A	p.Gln101Gln	synonymous_variant	Exon 5 of 5		NP_683708.1
TIRAP	NM_001039661.2	c.303G>A	p.Gln101Gln	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.303G>A	p.Gln101Gln	synonymous_variant	Exon 4 of 5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15979 AN: 152152 Hom.: 1091 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.116 AC: 28825 AN: 248808 Hom.: 1934 AF XY: 0.122 AC XY: 16420 AN XY: 134646

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.0696

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0121

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.140 AC: 204168 AN: 1461030 Hom.: 15303 Cov.: 34 AF XY: 0.140 AC XY: 102022 AN XY: 726746

Gnomad4 AFR exome AF: 0.0222

Gnomad4 AMR exome AF: 0.0727

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0200

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.105 AC: 15973 AN: 152270 Hom.: 1091 Cov.: 32 AF XY: 0.106 AC XY: 7869 AN XY: 74436

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.0962

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.115

Alfa AF: 0.131 Hom.: 1884

Bravo AF: 0.0972

Asia WGS AF: 0.0780 AC: 273 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	-0.61
CADD	Benign	3.7
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs3802814; hg19: chr11-126162607; COSMIC: COSV67024669; COSMIC: COSV67024669;