rs2149356

Variant names:

• chr9-117711921-T-G
• rs2149356
• NM_138554.5:c.261-468T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138554.5(TLR4):​c.261-468T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 151,998 control chromosomes in the GnomAD database, including 25,095 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (25095 hom., cov: 32)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 105 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]

TLR4 Gene-Disease associations (from GenCC):

• inflammatory bowel disease

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.677 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.261-468T>G		intron	N/A	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.141-468T>G		intron	N/A	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.-340-468T>G		intron	N/A	NP_612567.1	O00206-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.261-468T>G		intron	N/A	ENSP00000363089.5	O00206-1
	TLR4	ENST00000394487.5	TSL:1	c.141-468T>G		intron	N/A	ENSP00000377997.4	O00206-2
	ENSG00000285082	ENST00000697666.1		c.140+3192T>G		intron	N/A	ENSP00000513391.1	A0A8V8TMK6

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82541 AN: 151880 Hom.: 25102 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.598

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.543 AC: 82549 AN: 151998 Hom.: 25095 Cov.: 32 AF XY: 0.541 AC XY: 40179 AN XY: 74276

African (AFR) AF: 0.248 AC: 10268 AN: 41462

American (AMR) AF: 0.621 AC: 9480 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3207 AN: 5164

South Asian (SAS) AF: 0.627 AC: 3011 AN: 4802

European-Finnish (FIN) AF: 0.556 AC: 5875 AN: 10562

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46351 AN: 67964

Other (OTH) AF: 0.594 AC: 1255 AN: 2112

Alfa AF: 0.641 Hom.: 32176

Bravo AF: 0.539

Asia WGS AF: 0.602 AC: 2093 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		1.4
Mutation Taster		=100/0	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: rs2149356; hg19: chr9-120474199;