11-126290792-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 26 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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318777.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIRAP	NM_001318777.2	MANE Select	c.-92-11A>G		intron	N/A	NP_001305706.1
	TIRAP	NM_001318776.2		c.-92-11A>G		intron	N/A	NP_001305705.1
	TIRAP	NM_148910.3		c.-92-11A>G		intron	N/A	NP_683708.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIRAP	ENST00000392679.6	TSL:2 MANE Select	c.-92-11A>G		intron	N/A	ENSP00000376446.1
	TIRAP	ENST00000392678.7	TSL:1	c.-92-11A>G		intron	N/A	ENSP00000376445.3
	TIRAP	ENST00000392680.6	TSL:1	c.-92-11A>G		intron	N/A	ENSP00000376447.2

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

African (AFR) AF: 0.0862 AC: 2471 AN: 28652

American (AMR) AF: 0.0956 AC: 2107 AN: 22048

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 2973 AN: 22786

East Asian (EAS) AF: 0.0210 AC: 720 AN: 34230

South Asian (SAS) AF: 0.156 AC: 11241 AN: 72144

European-Finnish (FIN) AF: 0.144 AC: 6938 AN: 48166

Middle Eastern (MID) AF: 0.154 AC: 847 AN: 5494

European-Non Finnish (NFE) AF: 0.162 AC: 171689 AN: 1062244

Other (OTH) AF: 0.142 AC: 7929 AN: 55874

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

African (AFR) AF: 0.0946 AC: 3925 AN: 41486

American (AMR) AF: 0.111 AC: 1699 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3472

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5174

South Asian (SAS) AF: 0.156 AC: 750 AN: 4802

European-Finnish (FIN) AF: 0.149 AC: 1573 AN: 10568

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10926 AN: 67962

Other (OTH) AF: 0.141 AC: 298 AN: 2112

Alfa AF: 0.133 Hom.: 834

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.3
DANN	Benign	0.49
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1893352; hg19: chr11-126160687;