11-126292712-G-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.Gln101=) 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]

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/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.303G>A	p.Gln101=	synonymous_variant	4/5	ENST00000392679.6
TIRAP	NM_001318776.2	c.303G>A	p.Gln101=	synonymous_variant	4/4
TIRAP	NM_148910.3	c.303G>A	p.Gln101=	synonymous_variant	5/5
TIRAP	NM_001039661.2	c.303G>A	p.Gln101=	synonymous_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.303G>A	p.Gln101=	synonymous_variant	4/5	2	NM_001318777.2	P1

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

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	-0.61
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;