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rs4986791

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. 12/19 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

2
14

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]

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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 UniProt
TLR4NM_138554.5 linkuse as main transcriptc.1196C>T p.Thr399Ile missense_variant 3/3 ENST00000355622.8
TLR4NM_003266.4 linkuse as main transcriptc.1076C>T p.Thr359Ile missense_variant 4/4
TLR4NM_138557.3 linkuse as main transcriptc.596C>T p.Thr199Ile missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TLR4ENST00000355622.8 linkuse as main transcriptc.1196C>T p.Thr399Ile missense_variant 3/31 NM_138554.5 P1O00206-1
TLR4ENST00000394487.5 linkuse as main transcriptc.1076C>T p.Thr359Ile missense_variant 4/41 O00206-2
TLR4ENST00000472304.2 linkuse as main transcriptc.*930C>T 3_prime_UTR_variant 2/21

Frequencies

GnomAD3 genomes
AF:
0.0494
AC:
7511
AN:
152076
Hom.:
250
Cov.:
32
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.:
32
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.:
32
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:
73
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 providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio VillegasSep 01, 2023- -
TLR4 POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJul 18, 2002- -
not provided Other:1
not provided, no classification providedliterature onlyNEI 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
T
BayesDel_noAF
Benign
-0.60
Cadd
Benign
2.1
Dann
Uncertain
0.97
Eigen
Benign
-0.97
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.51
T;.;T
MetaRNN
Benign
0.0031
T;T;T
MetaSVM
Benign
-0.96
T
MutationTaster
Benign
9.8e-12
A;A
PrimateAI
Benign
0.37
T
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
T
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.

Other links and lift over

dbSNP: rs4986791; hg19: chr9-120475602; COSMIC: COSV62922311; COSMIC: COSV62922311; API