rs4986791

chr9-117713324-C-T

Variant summary

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

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 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
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided U:1 B:1 O:1
• 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]

ACMG classification

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
TLR4	NM_138554.5	c.1196C>T	p.Thr399Ile	missense_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.1076C>T	p.Thr359Ile	missense_variant	4/4
TLR4	NM_138557.3	c.596C>T	p.Thr199Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.1196C>T	p.Thr399Ile	missense_variant	3/3	1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.1076C>T	p.Thr359Ile	missense_variant	4/4	1
TLR4	ENST00000472304.2	c.*930C>T		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7511 AN: 152076 Hom.: 250 Cov.: 32

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

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

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

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:1 Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

- -

not provided Other:1

not provided, no classification provided

literature only

NEI 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

Other links and lift over

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