Genetic Variant TIRAP:p.Arg13Trp (chr11-126290931-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001318777.2(TIRAP):c.37C>T(p.Arg13Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,606,976 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 23 hom., cov: 32)

Exomes 𝑓: 0.019 ( 293 hom. )

Consequence

TIRAP
NM_001318777.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0780

Publications

18 publications found

Variant links:

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]

TIRAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018643737).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0148 (2258/152280) while in subpopulation NFE AF = 0.0213 (1448/68032). AF 95% confidence interval is 0.0204. There are 23 homozygotes in GnomAd4. There are 1079 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIRAP	NM_001318777.2 link	c.37C>T	p.Arg13Trp	missense_variant	Exon 3 of 5	ENST00000392679.6	NP_001305706.1	P58753-1A0A024R3M4
TIRAP	NM_001318776.2 link	c.37C>T	p.Arg13Trp	missense_variant	Exon 3 of 4		NP_001305705.1	P58753-2
TIRAP	NM_148910.3 link	c.37C>T	p.Arg13Trp	missense_variant	Exon 4 of 5		NP_683708.1	P58753-2
TIRAP	NM_001039661.2 link	c.37C>T	p.Arg13Trp	missense_variant	Exon 4 of 6		NP_001034750.1	P58753-1A0A024R3M4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6 link	c.37C>T	p.Arg13Trp	missense_variant	Exon 3 of 5	2	NM_001318777.2	ENSP00000376446.1		P58753-1

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2257

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0390

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.0141

AC:

3374

AN:

239306

AF XY:

0.0142

show subpopulations

Gnomad AFR exome

AF:

0.00317

Gnomad AMR exome

AF:

0.00563

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0373

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0186

AC:

27060

AN:

1454696

Hom.:

293

Cov.:

AF XY:

0.0182

AC XY:

13153

AN XY:

722950

show subpopulations

African (AFR)

AF:

0.00267

AC:

AN:

33394

American (AMR)

AF:

0.00618

AC:

272

AN:

44014

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

322

AN:

25756

East Asian (EAS)

AF:

0.000101

AC:

AN:

39634

South Asian (SAS)

AF:

0.00325

AC:

276

AN:

84940

European-Finnish (FIN)

AF:

0.0364

AC:

1922

AN:

52790

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0210

AC:

23273

AN:

1108292

Other (OTH)

AF:

0.0148

AC:

889

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1475

2951

4426

5902

7377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

858

1716

2574

3432

4290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0148

AC:

2258

AN:

152280

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1079

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00380

AC:

158

AN:

41570

American (AMR)

AF:

0.00909

AC:

139

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.000388

AC:

AN:

5160

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0390

AC:

414

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1448

AN:

68032

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0179

Hom.:

100

Bravo

AF:

0.0123

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00500

AC:

ESP6500EA

AF:

0.0194

AC:

167

ExAC

AF:

0.0134

AC:

1629

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.85

.;D;.

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

0.078

PrimateAI

Benign

0.26

PROVEAN

Benign

0.13

N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.98

D;.;D

Vest4

0.11

MPC

0.14

ClinPred

0.022

GERP RS

0.90

Varity_R

0.061

gMVP

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over