rs11536891

Positions:

• chr9-117717059-T-C

Variant summary

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

The NM_138554.5(TLR4):​c.*2411T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,116 control chromosomes in the GnomAD database, including 2,123 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 0.16 (2122 hom., cov: 32)
  • Exomes 𝑓: 0.21 (1 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*2411T>C		3_prime_UTR_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*2411T>C		3_prime_UTR_variant	4/4		NP_003257.1
TLR4	NM_138557.3	c.*2411T>C		3_prime_UTR_variant	2/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.*2411T>C		3_prime_UTR_variant	3/3	1	NM_138554.5	ENSP00000363089	P1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24591 AN: 151986 Hom.: 2112 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.214 AC: 3 AN: 14 Hom.: 1 Cov.: 0 AF XY: 0.300 AC XY: 3 AN XY: 10

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.162 AC: 24633 AN: 152102 Hom.: 2122 Cov.: 32 AF XY: 0.157 AC XY: 11700 AN XY: 74364

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0907

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.156

Alfa AF: 0.160 Hom.: 380

Bravo AF: 0.166

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11536891; hg19: chr9-120479337;