9-117713024-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/20 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: 𝑓 0.066 (378 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3299 hom.)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; protective no assertion criteria provided P:1 U:1 B:2
• Conservation: PhyloP100: 2.66

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]

ACMG classification

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
TLR4	NM_138554.5	c.896A>G	p.Asp299Gly	missense_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.776A>G	p.Asp259Gly	missense_variant	4/4
TLR4	NM_138557.3	c.296A>G	p.Asp99Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.896A>G	p.Asp299Gly	missense_variant	3/3	1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.776A>G	p.Asp259Gly	missense_variant	4/4	1
TLR4	ENST00000472304.2	c.*630A>G		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 10044 AN: 152074 Hom.: 378 Cov.: 32

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

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

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

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:1 Uncertain:1 Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

COPD, severe early onset Pathogenic:1

Likely risk allele, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Sep 01, 2023

Allele associated with the development of COPD secondary to tobacco smoke -

Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

-

- -

TLR4 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Pericementitis Benign:1

protective, no assertion criteria provided

case-control

OsteoImmunology Lab, Universidade de Sao Paulo

Dec 03, 2018

In 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

Other links and lift over

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