Menu
GeneBe

rs4986790

Variant summary

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

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,protective (no stars).

Frequency

Genomes: đť‘“ 0.066 ( 378 hom., cov: 32)
Exomes đť‘“: 0.062 ( 3299 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

16

Clinical Significance

Conflicting classifications of pathogenicity; protective no assertion criteria provided P:1U:1B:2

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]

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=0.0037297606).
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 UniProt
TLR4NM_138554.5 linkuse as main transcriptc.896A>G p.Asp299Gly missense_variant 3/3 ENST00000355622.8
TLR4NM_003266.4 linkuse as main transcriptc.776A>G p.Asp259Gly missense_variant 4/4
TLR4NM_138557.3 linkuse as main transcriptc.296A>G p.Asp99Gly missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TLR4ENST00000355622.8 linkuse as main transcriptc.896A>G p.Asp299Gly missense_variant 3/31 NM_138554.5 P1O00206-1
TLR4ENST00000394487.5 linkuse as main transcriptc.776A>G p.Asp259Gly missense_variant 4/41 O00206-2
TLR4ENST00000472304.2 linkuse as main transcriptc.*630A>G 3_prime_UTR_variant 2/21

Frequencies

GnomAD3 genomes
AF:
0.0660
AC:
10044
AN:
152074
Hom.:
378
Cov.:
32
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.:
32
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.:
32
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: Conflicting classifications of pathogenicity; protective
Submissions summary: Pathogenic:1Uncertain:1Benign:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

COPD, severe early onset Pathogenic:1
Likely risk allele, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio VillegasSep 01, 2023Allele associated with the development of COPD secondary to tobacco smoke -
Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1
Uncertain significance, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas-- -
TLR4 POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMSep 01, 2007- -
Pericementitis Benign:1
protective, no assertion criteria providedcase-controlOsteoImmunology Lab, Universidade de Sao PauloDec 03, 2018In 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 ‘susceptibility for inflammatory alveolar bone resorption’ [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
T
BayesDel_noAF
Benign
-0.51
Cadd
Benign
12
Dann
Benign
0.94
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.56
T;.;T
MetaRNN
Benign
0.0037
T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
7.6e-10
A;A
PrimateAI
Benign
0.29
T
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
T
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.

Other links and lift over

dbSNP: rs4986790; hg19: chr9-120475302; COSMIC: COSV62922307; COSMIC: COSV62922307; API