rs4986791

Positions:

chr9-117713324-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138554.5(TLR4):c.1196C>T(p.Thr399Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 1,613,894 control chromosomes in the GnomAD database, including 3,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.049 ( 250 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3347 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1O:1

Conservation

PhyloP100: -0.201

Variant links:

Genes affected

TLR4 (HGNC:11850): (toll like receptor 4) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

TLR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031039119).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TLR4	NM_138554.5 linkuse as main transcript	c.1196C>T	p.Thr399Ile	missense_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4 linkuse as main transcript	c.1076C>T	p.Thr359Ile	missense_variant	4/4
TLR4	NM_138557.3 linkuse as main transcript	c.596C>T	p.Thr199Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8 linkuse as main transcript	c.1196C>T	p.Thr399Ile	missense_variant	3/3	1	NM_138554.5	P1	O00206-1
TLR4	ENST00000394487.5 linkuse as main transcript	c.1076C>T	p.Thr359Ile	missense_variant	4/4	1			O00206-2
TLR4	ENST00000472304.2 linkuse as main transcript	c.*930C>T		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.0494

AC:

7511

AN:

152076

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0408

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.0963

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0642

Gnomad OTH

AF:

0.0451

GnomAD3 exomes

AF:

0.0566

AC:

14176

AN:

250350

Hom.:

537

AF XY:

0.0602

AC XY:

8143

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.0266

Gnomad ASJ exome

AF:

0.0511

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.0576

Gnomad OTH exome

AF:

0.0576

GnomAD4 exome

AF:

0.0625

AC:

91406

AN:

1461700

Hom.:

3347

Cov.:

AF XY:

0.0636

AC XY:

46272

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0149

Gnomad4 AMR exome

AF:

0.0282

Gnomad4 ASJ exome

AF:

0.0519

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.102

Gnomad4 NFE exome

AF:

0.0626

Gnomad4 OTH exome

AF:

0.0648

GnomAD4 genome

AF:

0.0493

AC:

7509

AN:

152194

Hom.:

250

Cov.:

AF XY:

0.0525

AC XY:

3908

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.0407

Gnomad4 ASJ

AF:

0.0513

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.113

Gnomad4 FIN

AF:

0.0963

Gnomad4 NFE

AF:

0.0642

Gnomad4 OTH

AF:

0.0446

Alfa

AF:

0.0562

Hom.:

550

Bravo

AF:

0.0409

TwinsUK

AF:

0.0510

AC:

189

ALSPAC

AF:

0.0563

AC:

217

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0626

AC:

538

ExAC

AF:

0.0550

AC:

6681

Asia WGS

AF:

0.0640

AC:

221

AN:

3474

EpiCase

AF:

0.0612

EpiControl

AF:

0.0576

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

COPD, severe early onset

Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Sep 01, 2023

- -

TLR4 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 18, 2002

- -

not provided

Other:1

not provided, no classification provided

literature only

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.60

CADD

Benign

2.1

DANN

Uncertain

0.97

DEOGEN2

Benign

0.25

.;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.51

T;.;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

.;L;L

MutationTaster

Benign

9.8e-12

A;A

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

N;.;N

REVEL

Benign

0.016

Sift

Uncertain

0.024

D;.;D

Sift4G

Benign

0.090

T;.;T

Polyphen

0.18

.;B;B

Vest4

0.063

MPC

0.12

ClinPred

0.0079

GERP RS

0.43

Varity_R

0.21

gMVP

0.40

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over