rs4986790

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_138554.5(TLR4):c.896A>G(p.Asp299Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,613,856 control chromosomes in the GnomAD database, including 3,677 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 Benign (★).

Frequency

Genomes: 𝑓 0.066 ( 378 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3299 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter P:1U:1B:3

Conservation

PhyloP100: 2.66

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037297606).

BP6

Variant 9-117713024-A-G is Benign according to our data. Variant chr9-117713024-A-G is described in ClinVar as [Benign]. Clinvar id is 6660.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-117713024-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TLR4	NM_138554.5 linkuse as main transcript	c.896A>G	p.Asp299Gly	missense_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 linkuse as main transcript	c.776A>G	p.Asp259Gly	missense_variant	4/4		NP_003257.1
TLR4	NM_138557.3 linkuse as main transcript	c.296A>G	p.Asp99Gly	missense_variant	2/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 linkuse as main transcript	c.896A>G	p.Asp299Gly	missense_variant	3/3	1	NM_138554.5	ENSP00000363089	P1	O00206-1
TLR4	ENST00000394487.5 linkuse as main transcript	c.776A>G	p.Asp259Gly	missense_variant	4/4	1		ENSP00000377997		O00206-2
TLR4	ENST00000472304.2 linkuse as main transcript	c.*630A>G		3_prime_UTR_variant	2/2	1		ENSP00000496429

Frequencies

GnomAD3 genomes

AF:

0.0660

AC:

10044

AN:

152074

Hom.:

378

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0773

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0461

Gnomad ASJ

AF:

0.0697

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.0948

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0614

Gnomad OTH

AF:

0.0585

GnomAD3 exomes

AF:

0.0605

AC:

15187

AN:

250890

Hom.:

584

AF XY:

0.0629

AC XY:

8525

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.0732

Gnomad AMR exome

AF:

0.0290

Gnomad ASJ exome

AF:

0.0658

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.114

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.0548

Gnomad OTH exome

AF:

0.0612

GnomAD4 exome

AF:

0.0621

AC:

90797

AN:

1461664

Hom.:

3299

Cov.:

AF XY:

0.0632

AC XY:

45973

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0793

Gnomad4 AMR exome

AF:

0.0310

Gnomad4 ASJ exome

AF:

0.0658

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.101

Gnomad4 NFE exome

AF:

0.0592

Gnomad4 OTH exome

AF:

0.0672

GnomAD4 genome

AF:

0.0660

AC:

10042

AN:

152192

Hom.:

378

Cov.:

AF XY:

0.0684

AC XY:

5088

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0771

Gnomad4 AMR

AF:

0.0460

Gnomad4 ASJ

AF:

0.0697

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.0948

Gnomad4 NFE

AF:

0.0614

Gnomad4 OTH

AF:

0.0579

Alfa

AF:

0.0580

Hom.:

519

Bravo

AF:

0.0596

TwinsUK

AF:

0.0494

AC:

183

ALSPAC

AF:

0.0506

AC:

195

ESP6500AA

AF:

0.0713

AC:

314

ESP6500EA

AF:

0.0601

AC:

517

ExAC

AF:

0.0599

AC:

7267

Asia WGS

AF:

0.0640

AC:

221

AN:

3476

EpiCase

AF:

0.0583

EpiControl

AF:

0.0551

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

COPD, severe early onset

Pathogenic:1

Likely risk allele, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Sep 01, 2023

Allele associated with the development of COPD secondary to tobacco smoke -

Susceptibility to severe coronavirus disease (COVID-19)

Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

- -

TLR4 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Pericementitis

Benign:1

protective, no assertion criteria provided

case-control

OsteoImmunology Lab, Universidade de Sao Paulo

Dec 03, 2018

In an exploratory population (N=570, 186 cases/ 384 controls), rs4986790 demonstrated a significant protective effect for the phenotype of chronic periodontitis [OR 0.3315, CI 0.14-0.75, p-value 0.005] . The association analysis combining the exploratory and three independent validation populations (N=1410; 528 cases and 882 controls) demonstrated a significant protective effect of the polymorphic allele for the phenotype â€˜susceptibility for inflammatory alveolar bone resorptionâ€™ [OR 0.57, CI 0.38-0.85, p-value 0.005]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.32

.;T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.56

T;.;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;M

MutationTaster

Benign

7.6e-10

A;A

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

N;.;N

REVEL

Benign

0.079

Sift

Benign

0.093

T;.;T

Sift4G

Benign

0.085

T;.;T

Polyphen

0.026

.;B;B

Vest4

0.070

MPC

0.11

ClinPred

0.023

GERP RS

4.6

Varity_R

0.19

gMVP

0.49

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