Variant 11-126292998-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2 link	c.589G>A	p.Val197Ile	missense_variant	4/5	ENST00000392679.6	NP_001305706.1	P58753-1A0A024R3M4
TIRAP	NM_001318776.2 link	c.589G>A	p.Val197Ile	missense_variant	4/4		NP_001305705.1	P58753-2
TIRAP	NM_148910.3 link	c.589G>A	p.Val197Ile	missense_variant	5/5		NP_683708.1	P58753-2
TIRAP	NM_001039661.2 link	c.589G>A	p.Val197Ile	missense_variant	5/6		NP_001034750.1	P58753-1A0A024R3M4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6 link	c.589G>A	p.Val197Ile	missense_variant	4/5	2	NM_001318777.2	ENSP00000376446.1		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

GnomAD3 exomes

AF:

0.00231

AC:

577

AN:

249838

Hom.:

AF XY:

0.00176

AC XY:

238

AN XY:

135502

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 SAS 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

Gnomad4 AFR exome

AF:

0.0260

Gnomad4 AMR exome

AF:

0.00353

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000371

Gnomad4 OTH exome

AF:

0.00267

GnomAD4 genome

AF:

0.00760

AC:

1158

AN:

152326

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

520

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0247

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00190

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

T;.;T

Eigen

Benign

0.083

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

.;T;.

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.12

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.88

P;.;P

Vest4

0.10

MVP

0.46

MPC

0.21

ClinPred

0.031

GERP RS

3.9

Varity_R

0.085

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over