rs8177400

chr11-126292695-G-Achr11-126292695-G-Cchr11-126292695-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_001318777.2(TIRAP):c.286G>A(p.Asp96Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,862 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (15 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 8.55

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 -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.037235945).
• BP6: Variant 11-126292695-G-A is Benign according to our data. Variant chr11-126292695-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1285058.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-126292695-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.286G>A	p.Asp96Asn	missense_variant	4/5	ENST00000392679.6
TIRAP	NM_001318776.2	c.286G>A	p.Asp96Asn	missense_variant	4/4
TIRAP	NM_148910.3	c.286G>A	p.Asp96Asn	missense_variant	5/5
TIRAP	NM_001039661.2	c.286G>A	p.Asp96Asn	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.286G>A	p.Asp96Asn	missense_variant	4/5	2	NM_001318777.2	P1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00276 AC: 691 AN: 250018 Hom.: 4 AF XY: 0.00313 AC XY: 423 AN XY: 135254

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00514

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00227 AC: 3316 AN: 1461526 Hom.: 15 Cov.: 31 AF XY: 0.00250 AC XY: 1821 AN XY: 727032

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74490

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00235

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00486

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MVP		0.76
MPC		0.22
ClinPred		0.040	T
GERP RS		5.4
Varity_R		0.96
gMVP		0.85

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: rs8177400; hg19: chr11-126162590;