rs4986790

Variant names:

• chr9-117713024-A-G
• rs4986790
• NM_138554.5:c.896A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-117713024-A-G
• chr9-117713024-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.066 (378 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3299 hom.)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:3
• Conservation: PhyloP100: 2.66
• Publications: 1699 publications found

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]

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037297606).
• BP6: Variant 9-117713024-A-G is Benign according to our data. Variant chr9-117713024-A-G is described in ClinVar as Benign. ClinVar VariationId is 6660.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.896A>G	p.Asp299Gly	missense	Exon 3 of 3	NP_612564.1
	TLR4	NM_003266.4		c.776A>G	p.Asp259Gly	missense	Exon 4 of 4	NP_003257.1
	TLR4	NM_138557.3		c.296A>G	p.Asp99Gly	missense	Exon 2 of 2	NP_612567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.896A>G	p.Asp299Gly	missense	Exon 3 of 3	ENSP00000363089.5
	TLR4	ENST00000394487.5	TSL:1	c.776A>G	p.Asp259Gly	missense	Exon 4 of 4	ENSP00000377997.4
	TLR4	ENST00000472304.2	TSL:1	c.*630A>G		3_prime_UTR	Exon 2 of 2	ENSP00000496429.1

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

GnomAD2 exomes AF: 0.0605 AC: 15187 AN: 250890 AF XY: 0.0629

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 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

African (AFR) AF: 0.0793 AC: 2653 AN: 33474

American (AMR) AF: 0.0310 AC: 1387 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0658 AC: 1719 AN: 26130

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39674

South Asian (SAS) AF: 0.110 AC: 9464 AN: 86248

European-Finnish (FIN) AF: 0.101 AC: 5377 AN: 53416

Middle Eastern (MID) AF: 0.0466 AC: 269 AN: 5768

European-Non Finnish (NFE) AF: 0.0592 AC: 65857 AN: 1111856

Other (OTH) AF: 0.0672 AC: 4057 AN: 60384

GnomAD4 genome AF: 0.0660 AC: 10042 AN: 152192 Hom.: 378 Cov.: 32 AF XY: 0.0684 AC XY: 5088 AN XY: 74394

African (AFR) AF: 0.0771 AC: 3202 AN: 41532

American (AMR) AF: 0.0460 AC: 703 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 242 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.120 AC: 579 AN: 4812

European-Finnish (FIN) AF: 0.0948 AC: 1004 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0614 AC: 4175 AN: 68008

Other (OTH) AF: 0.0579 AC: 122 AN: 2108

Alfa AF: 0.0581 Hom.: 1085

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: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

COPD, severe early onset Pathogenic:1

Sep 01, 2023

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

Allele associated with the development of COPD secondary to tobacco smoke

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

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

Sep 01, 2007

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Pericementitis Benign:1

Dec 03, 2018

OsteoImmunology Lab, Universidade de Sao Paulo

Significance: protective

Review Status: no assertion criteria provided

Collection Method: case-control

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 v4.9

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
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.079
Sift	Benign	0.093	T
Sift4G	Benign	0.085	T
Polyphen		0.026	B
Vest4		0.070
MPC		0.11
ClinPred		0.023	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.49
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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