11-126293796-A-G

Variant names:

• chr11-126293796-A-G
• rs611953
• ENST00000479770.2:n.*109A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000479770.2(TIRAP):​n.*109A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 1,253,056 control chromosomes in the GnomAD database, including 380,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (41535 hom., cov: 32)
  • Exomes 𝑓: 0.78 (338873 hom.)
• Consequence: TIRAP ENST00000479770.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0640
• Publications: 22 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]

ENSG00000254905 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-126293796-A-G is Benign according to our data. Variant chr11-126293796-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688423.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.*109A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001039661.2	c.*109A>G		3_prime_UTR_variant	Exon 6 of 6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.*109A>G		3_prime_UTR_variant	Exon 5 of 5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110850 AN: 151992 Hom.: 41498 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.723

GnomAD2 exomes AF: 0.796 AC: 189709 AN: 238380 AF XY: 0.798

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.736

Gnomad EAS exome AF: 0.989

Gnomad FIN exome AF: 0.784

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.781 AC: 859947 AN: 1100946 Hom.: 338873 Cov.: 14 AF XY: 0.784 AC XY: 442300 AN XY: 563996

African (AFR) AF: 0.548 AC: 14635 AN: 26684

American (AMR) AF: 0.852 AC: 36745 AN: 43142

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 17548 AN: 23864

East Asian (EAS) AF: 0.994 AC: 37570 AN: 37796

South Asian (SAS) AF: 0.865 AC: 68077 AN: 78726

European-Finnish (FIN) AF: 0.780 AC: 40277 AN: 51618

Middle Eastern (MID) AF: 0.701 AC: 3565 AN: 5082

European-Non Finnish (NFE) AF: 0.769 AC: 604116 AN: 785544

Other (OTH) AF: 0.772 AC: 37414 AN: 48490

GnomAD4 genome AF: 0.729 AC: 110940 AN: 152110 Hom.: 41535 Cov.: 32 AF XY: 0.739 AC XY: 54978 AN XY: 74350

African (AFR) AF: 0.563 AC: 23359 AN: 41468

American (AMR) AF: 0.801 AC: 12255 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2531 AN: 3466

East Asian (EAS) AF: 0.991 AC: 5121 AN: 5166

South Asian (SAS) AF: 0.871 AC: 4196 AN: 4820

European-Finnish (FIN) AF: 0.800 AC: 8469 AN: 10586

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52554 AN: 67988

Other (OTH) AF: 0.726 AC: 1535 AN: 2114

Alfa AF: 0.727 Hom.: 19448

Bravo AF: 0.719

Asia WGS AF: 0.912 AC: 3171 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 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.61
PhyloP100		-0.064
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs611953; hg19: chr11-126163691;