rs12344353

Variant names:

• chr9-117706371-T-C
• rs12344353
• NM_138554.5:c.93+1806T>C

Variant summary

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

The NM_138554.5(TLR4):​c.93+1806T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 152,240 control chromosomes in the GnomAD database, including 614 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 0.081 (614 hom., cov: 32)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.882
• Publications: 13 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.93+1806T>C		intron	N/A	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.-148+1806T>C		intron	N/A	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.-341+1806T>C		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.93+1806T>C		intron	N/A	ENSP00000363089.5	O00206-1
	TLR4	ENST00000394487.5	TSL:1	c.-148+1806T>C		intron	N/A	ENSP00000377997.4	O00206-2
	ENSG00000285082	ENST00000697666.1		c.-148+1806T>C		intron	N/A	ENSP00000513391.1	A0A8V8TMK6

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12250 AN: 152122 Hom.: 616 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0950

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0720

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

GnomAD4 genome AF: 0.0805 AC: 12262 AN: 152240 Hom.: 614 Cov.: 32 AF XY: 0.0829 AC XY: 6173 AN XY: 74430

African (AFR) AF: 0.128 AC: 5309 AN: 41520

American (AMR) AF: 0.0531 AC: 812 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.115 AC: 555 AN: 4826

European-Finnish (FIN) AF: 0.0950 AC: 1007 AN: 10596

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4226 AN: 68020

Other (OTH) AF: 0.0712 AC: 150 AN: 2106

Alfa AF: 0.0653 Hom.: 132

Bravo AF: 0.0760

Asia WGS AF: 0.0710 AC: 246 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.70
PhyloP100		-0.88
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: rs12344353; hg19: chr9-120468649;