rs11536898

chr9-117717932-C-A

Variant summary

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

The NM_138554.5(TLR4):c.*3284C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,054 control chromosomes in the GnomAD database, including 1,682 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 0.14 (1682 hom., cov: 32)
  • Exomes 𝑓: 0.15 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196

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 (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.*3284C>A		3_prime_UTR_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.*3284C>A		3_prime_UTR_variant	4/4
TLR4	NM_138557.3	c.*3284C>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.*3284C>A		3_prime_UTR_variant	3/3	1	NM_138554.5	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21531 AN: 151916 Hom.: 1674 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0848

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.150 AC: 3 AN: 20 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.188

GnomAD4 genome AF: 0.142 AC: 21570 AN: 152034 Hom.: 1682 Cov.: 32 AF XY: 0.138 AC XY: 10279 AN XY: 74334

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0848

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.130

Alfa AF: 0.131 Hom.: 300

Bravo AF: 0.145

Asia WGS AF: 0.117 AC: 408 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.99
Dann	Benign	0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11536898; hg19: chr9-120480210;