rs3802813

chr11-126292573-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001318777.2(TIRAP):c.164G>A(p.Ser55Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,613,986 control chromosomes in the GnomAD database, including 3,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.062 (417 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2835 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.473

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012226701).
• BP6: Variant 11-126292573-G-A is Benign according to our data. Variant chr11-126292573-G-A is described in ClinVar as [Benign]. Clinvar id is 2688471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.164G>A	p.Ser55Asn	missense_variant	4/5	ENST00000392679.6
TIRAP	NM_001318776.2	c.164G>A	p.Ser55Asn	missense_variant	4/4
TIRAP	NM_148910.3	c.164G>A	p.Ser55Asn	missense_variant	5/5
TIRAP	NM_001039661.2	c.164G>A	p.Ser55Asn	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.164G>A	p.Ser55Asn	missense_variant	4/5	2	NM_001318777.2	P1

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9420 AN: 152056 Hom.: 416 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0802

Gnomad FIN AF: 0.0665

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0647

GnomAD3 exomes AF: 0.0776 AC: 19476 AN: 251124 Hom.: 1221 AF XY: 0.0726 AC XY: 9850 AN XY: 135758

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0368

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.0688

Gnomad FIN exome AF: 0.0687

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0636

GnomAD4 exome AF: 0.0496 AC: 72462 AN: 1461812 Hom.: 2835 Cov.: 32 AF XY: 0.0498 AC XY: 36231 AN XY: 727200

Gnomad4 AFR exome AF: 0.0562

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.0376

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.0704

Gnomad4 FIN exome AF: 0.0679

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.0620 AC: 9433 AN: 152174 Hom.: 417 Cov.: 32 AF XY: 0.0657 AC XY: 4890 AN XY: 74386

Gnomad4 AFR AF: 0.0547

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.0790

Gnomad4 FIN AF: 0.0665

Gnomad4 NFE AF: 0.0413

Gnomad4 OTH AF: 0.0654

Alfa AF: 0.0465 Hom.: 525

Bravo AF: 0.0651

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.0618 AC: 272

ESP6500EA AF: 0.0370 AC: 318

ExAC AF: 0.0733 AC: 8899

Asia WGS AF: 0.143 AC: 497 AN: 3478

EpiCase AF: 0.0395

EpiControl AF: 0.0397

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

TIRAP-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.5
Dann	Benign	0.57
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.88	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.025
MPC		0.027
ClinPred		0.00084	T
GERP RS		-2.1
Varity_R		0.044
gMVP		0.33

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: rs3802813; hg19: chr11-126162468;