NM_001318777.2:c.589G>A

Variant names:

Variant summary

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

The NM_001318777.2(TIRAP):c.589G>A(p.Val197Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,176 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0076 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 14 hom. )

Consequence

TIRAP
NM_001318777.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.51

Publications

14 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:

ENSG00000254905 (HGNC:):

ENSG00000254905 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=0.004019141).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0076 (1158/152326) while in subpopulation AFR AF = 0.0247 (1027/41572). AF 95% confidence interval is 0.0234. There are 14 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318777.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIRAP	NM_001318777.2	MANE Select	c.589G>A	p.Val197Ile	missense	Exon 4 of 5	NP_001305706.1	P58753-1
TIRAP	NM_001318776.2		c.589G>A	p.Val197Ile	missense	Exon 4 of 4	NP_001305705.1	P58753-2
TIRAP	NM_148910.3		c.589G>A	p.Val197Ile	missense	Exon 5 of 5	NP_683708.1	P58753-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIRAP	ENST00000392679.6	TSL:2 MANE Select	c.589G>A	p.Val197Ile	missense	Exon 4 of 5	ENSP00000376446.1	P58753-1
TIRAP	ENST00000392678.7	TSL:1	c.589G>A	p.Val197Ile	missense	Exon 5 of 5	ENSP00000376445.3	P58753-2
TIRAP	ENST00000392680.6	TSL:1	c.589G>A	p.Val197Ile	missense	Exon 5 of 6	ENSP00000376447.2	P58753-1

Frequencies

GnomAD3 genomes

AF:

0.00754

AC:

1147

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00231

AC:

577

AN:

249838

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000459

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00114

AC:

1668

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000971

AC XY:

706

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0260

AC:

871

AN:

33480

American (AMR)

AF:

0.00353

AC:

158

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000371

AC:

412

AN:

1111984

Other (OTH)

AF:

0.00267

AC:

161

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00760

AC:

1158

AN:

152326

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

520

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0247

AC:

1027

AN:

41572

American (AMR)

AF:

0.00451

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68020

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00323

Hom.:

Bravo

AF:

0.00864

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0264

AC:

116

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00259

AC:

314

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000415

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Benign

0.083

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

3.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.12

REVEL

Benign

0.11

Sift

Benign

0.45

Sift4G

Benign

0.43

Polyphen

0.88

Vest4

0.10

MVP

0.46

MPC

0.21

ClinPred

0.031

GERP RS

3.9

Varity_R

0.085

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over