11-126291595-T-C

Position:

• chr11-126291595-T-C

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.67+634T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 462,890 control chromosomes in the GnomAD database, including 140,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (41587 hom., cov: 33)
  • Exomes 𝑓: 0.79 (98951 hom.)
• Consequence: TIRAP NM_001318777.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.832

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=-0.89).
• BP6: Variant 11-126291595-T-C is Benign according to our data. Variant chr11-126291595-T-C is described in ClinVar as [Benign]. Clinvar id is 2688416.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/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.67+634T>C		intron_variant		ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.67+634T>C		intron_variant			NP_001305705.1
TIRAP	NM_148910.3	c.67+634T>C		intron_variant			NP_683708.1
TIRAP	NM_001039661.2	c.67+634T>C		intron_variant			NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.67+634T>C		intron_variant		2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110691 AN: 151814 Hom.: 41551 Cov.: 33

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.720

GnomAD4 exome AF: 0.793 AC: 246731 AN: 310960 Hom.: 98951 Cov.: 4 AF XY: 0.801 AC XY: 140999 AN XY: 176088

Gnomad4 AFR exome AF: 0.552

Gnomad4 AMR exome AF: 0.854

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.864

Gnomad4 FIN exome AF: 0.779

Gnomad4 NFE exome AF: 0.768

Gnomad4 OTH exome AF: 0.771

GnomAD4 genome AF: 0.729 AC: 110778 AN: 151930 Hom.: 41587 Cov.: 33 AF XY: 0.739 AC XY: 54878 AN XY: 74274

Gnomad4 AFR AF: 0.562

Gnomad4 AMR AF: 0.801

Gnomad4 ASJ AF: 0.731

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.870

Gnomad4 FIN AF: 0.799

Gnomad4 NFE AF: 0.773

Gnomad4 OTH AF: 0.723

Alfa AF: 0.735 Hom.: 5601

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

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 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	-0.89
CADD	Benign	0.048
DANN	Benign	0.29

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: rs614700; hg19: chr11-126161490;