rs2149356

Positions:

• chr9-117711921-T-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.261-468T>G		intron_variant		ENST00000355622.8
TLR4	NM_003266.4	c.141-468T>G		intron_variant
TLR4	NM_138557.3	c.-340-468T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.261-468T>G		intron_variant		1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.141-468T>G		intron_variant		1
TLR4	ENST00000472304.2	c.94-468T>G		intron_variant		1

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

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.627

Gnomad4 FIN AF: 0.556

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.594

Alfa AF: 0.656 Hom.: 25890

Bravo AF: 0.539

Asia WGS AF: 0.602 AC: 2093 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2149356; hg19: chr9-120474199;