rs4986791

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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

Scores

Clinical Significance

Benign criteria provided, single submitter U:1B:2O:1

Conservation

PhyloP100: -0.201

Publications

1122 publications found

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:

ENSG00000285082 (HGNC:):

ENSG00000285082 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 6661.Status of the report is criteria_provided_single_submitter, 1 stars.

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 rank	MANE	Protein
TLR4	NM_138554.5 link	c.1196C>T	p.Thr399Ile	missense_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 link	c.1076C>T	p.Thr359Ile	missense_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3 link	c.596C>T	p.Thr199Ile	missense_variant	Exon 2 of 2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 link	c.1196C>T	p.Thr399Ile	missense_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1 link	c.140+4595C>T		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes

AF:

0.0494

AC:

7511

AN:

152076

Hom.:

250

Cov.:

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

GnomAD2 exomes

AF:

0.0566

AC:

14176

AN:

250350

AF XY:

0.0602

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 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.:

AF XY:

0.0636

AC XY:

46272

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.0149

AC:

499

AN:

33476

American (AMR)

AF:

0.0282

AC:

1261

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

1355

AN:

26132

East Asian (EAS)

AF:

0.000378

AC:

AN:

39674

South Asian (SAS)

AF:

0.105

AC:

9062

AN:

86256

European-Finnish (FIN)

AF:

0.102

AC:

5432

AN:

53372

Middle Eastern (MID)

AF:

0.0473

AC:

273

AN:

5768

European-Non Finnish (NFE)

AF:

0.0626

AC:

69596

AN:

1111952

Other (OTH)

AF:

0.0648

AC:

3913

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

5579

11159

16738

22318

27897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2564

5128

7692

10256

12820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0493

AC:

7509

AN:

152194

Hom.:

250

Cov.:

AF XY:

0.0525

AC XY:

3908

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0154

AC:

640

AN:

41552

American (AMR)

AF:

0.0407

AC:

622

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3468

East Asian (EAS)

AF:

0.000967

AC:

AN:

5168

South Asian (SAS)

AF:

0.113

AC:

544

AN:

4824

European-Finnish (FIN)

AF:

0.0963

AC:

1019

AN:

10584

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0642

AC:

4364

AN:

68004

Other (OTH)

AF:

0.0446

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

357

715

1072

1430

1787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0542

Hom.:

1077

Bravo

AF:

0.0409

TwinsUK

AF:

0.0510

AC:

189

ALSPAC

AF:

0.0563

AC:

217

ESP6500AA

AF:

0.0166

AC:

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: Benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

COPD, severe early onset

Uncertain:1

Sep 01, 2023

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

TLR4 POLYMORPHISM

Benign:1

Jul 18, 2002

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.60

CADD

Benign

2.1

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.25

.;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.51

T;.;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

.;L;L

PhyloP100

-0.20

PrimateAI

Benign

0.37

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

GERP RS

0.43

Varity_R

0.21

gMVP

0.40

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over