rs4986791
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1
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 Benign (★).
Frequency
Genomes: 𝑓 0.049 ( 250 hom., cov: 32)
Exomes 𝑓: 0.063 ( 3347 hom. )
Consequence
TLR4
NM_138554.5 missense
NM_138554.5 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: -0.201
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0031039119).
BP6
Variant 9-117713324-C-T is Benign according to our data. Variant chr9-117713324-C-T is described in ClinVar as [Benign]. Clinvar id is 6661.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-117713324-C-T is described in Lovd as [Likely_benign].
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TLR4 | NM_138554.5 | c.1196C>T | p.Thr399Ile | missense_variant | 3/3 | ENST00000355622.8 | NP_612564.1 | |
TLR4 | NM_003266.4 | c.1076C>T | p.Thr359Ile | missense_variant | 4/4 | NP_003257.1 | ||
TLR4 | NM_138557.3 | c.596C>T | p.Thr199Ile | missense_variant | 2/2 | NP_612567.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TLR4 | ENST00000355622.8 | c.1196C>T | p.Thr399Ile | missense_variant | 3/3 | 1 | NM_138554.5 | ENSP00000363089 | P1 | |
TLR4 | ENST00000394487.5 | c.1076C>T | p.Thr359Ile | missense_variant | 4/4 | 1 | ENSP00000377997 | |||
TLR4 | ENST00000472304.2 | c.*930C>T | 3_prime_UTR_variant | 2/2 | 1 | ENSP00000496429 |
Frequencies
GnomAD3 genomes AF: 0.0494 AC: 7511AN: 152076Hom.: 250 Cov.: 32
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GnomAD3 exomes AF: 0.0566 AC: 14176AN: 250350Hom.: 537 AF XY: 0.0602 AC XY: 8143AN XY: 135366
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GnomAD4 exome AF: 0.0625 AC: 91406AN: 1461700Hom.: 3347 Cov.: 32 AF XY: 0.0636 AC XY: 46272AN XY: 727150
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GnomAD4 genome AF: 0.0493 AC: 7509AN: 152194Hom.: 250 Cov.: 32 AF XY: 0.0525 AC XY: 3908AN XY: 74418
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189
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217
ESP6500AA
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1Other:1
not provided, no classification provided | literature only | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | - | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
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 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;.;T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;L
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Uncertain
D;.;D
Sift4G
Benign
T;.;T
Polyphen
0.18
.;B;B
Vest4
MPC
0.12
ClinPred
T
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at