rs11536869

Variant names:

• chr9-117707554-A-G
• rs11536869
• NM_138554.5:c.94-1009A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_138554.5(TLR4):​c.94-1009A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 152,334 control chromosomes in the GnomAD database, including 66 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 0.023 (66 hom., cov: 33)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3496/152334) while in subpopulation NFE AF = 0.0355 (2414/68028). AF 95% confidence interval is 0.0343. There are 66 homozygotes in GnomAd4. There are 1537 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.94-1009A>G		intron_variant	Intron 1 of 2	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.-147-645A>G		intron_variant	Intron 1 of 3		NP_003257.1
TLR4	NM_138557.3	c.-341+2989A>G		intron_variant	Intron 1 of 1		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.94-1009A>G		intron_variant	Intron 1 of 2	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.-147-645A>G		intron_variant	Intron 1 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3500 AN: 152216 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0277

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

GnomAD4 genome AF: 0.0229 AC: 3496 AN: 152334 Hom.: 66 Cov.: 33 AF XY: 0.0206 AC XY: 1537 AN XY: 74494

African (AFR) AF: 0.00628 AC: 261 AN: 41582

American (AMR) AF: 0.0269 AC: 411 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00827 AC: 40 AN: 4834

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2414 AN: 68028

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0332 Hom.: 212

Bravo AF: 0.0243

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs11536869; hg19: chr9-120469832;