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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 0.066 in 152074 control chromosomes in the gnomAD Genomes database, including 378 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 interpretations of pathogenicity,protective (no stars).

Frequency

Genomes: đť‘“ 0.066 ( 378 hom., cov: 32)
Exomes đť‘“: 0.061 ( 584 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

16

Clinical Significance

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

Conservation

PhyloP100: 2.66

Links

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
?
GnomAd 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
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
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 interpretations 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;