NM_001318777.2:c.-92-11A>G

Variant names:

• chr11-126290792-A-G
• rs1893352
• NM_001318777.2:c.-92-11A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001318777.2(TIRAP):​c.-92-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,503,694 control chromosomes in the GnomAD database, including 18,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1472 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16623 hom.)
• Consequence: TIRAP NM_001318777.2 intron
• Scores: Splicing: ADA: 0.00002569
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.368

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-126290792-A-G is Benign according to our data. Variant chr11-126290792-A-G is described in ClinVar as [Benign]. Clinvar id is 2688499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.-92-11A>G		intron_variant	Intron 2 of 4	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.-92-11A>G		intron_variant	Intron 2 of 3		NP_001305705.1
TIRAP	NM_148910.3	c.-92-11A>G		intron_variant	Intron 3 of 4		NP_683708.1
TIRAP	NM_001039661.2	c.-92-11A>G		intron_variant	Intron 3 of 5		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.-92-11A>G		intron_variant	Intron 2 of 4	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20057 AN: 151938 Hom.: 1470 Cov.: 32

Gnomad AFR AF: 0.0945

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.153 AC: 206915 AN: 1351638 Hom.: 16623 Cov.: 31 AF XY: 0.153 AC XY: 101860 AN XY: 666580

Gnomad4 AFR exome AF: 0.0862

Gnomad4 AMR exome AF: 0.0956

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.0210

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.132 AC: 20064 AN: 152056 Hom.: 1472 Cov.: 32 AF XY: 0.132 AC XY: 9834 AN XY: 74298

Gnomad4 AFR AF: 0.0946

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0151

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.141

Alfa AF: 0.131 Hom.: 750

Bravo AF: 0.126

Asia WGS AF: 0.0860 AC: 302 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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.3
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs1893352; hg19: chr11-126160687;