11-126290792-A-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 splice polypyrimidine tract, 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 splice_polypyrimidine_tract, 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/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.-92-11A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000392679.6
TIRAP	NM_001039661.2	c.-92-11A>G		splice_polypyrimidine_tract_variant, intron_variant
TIRAP	NM_001318776.2	c.-92-11A>G		splice_polypyrimidine_tract_variant, intron_variant
TIRAP	NM_148910.3	c.-92-11A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.-92-11A>G		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001318777.2	P1

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

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 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;