rs5030728

chr9-117712004-G-Achr9-117712004-G-T

Variant summary

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

The NM_138554.5(TLR4):c.261-385G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,130 control chromosomes in the GnomAD database, including 4,568 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 0.23 (4568 hom., cov: 33)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.538

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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.261-385G>A		intron_variant		ENST00000355622.8
TLR4	NM_003266.4	c.141-385G>A		intron_variant
TLR4	NM_138557.3	c.-340-385G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.261-385G>A		intron_variant		1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.141-385G>A		intron_variant		1
TLR4	ENST00000472304.2	c.94-385G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35087 AN: 152012 Hom.: 4567 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.231 AC: 35092 AN: 152130 Hom.: 4568 Cov.: 33 AF XY: 0.226 AC XY: 16820 AN XY: 74360

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.246

Alfa AF: 0.253 Hom.: 890

Bravo AF: 0.227

Asia WGS AF: 0.102 AC: 359 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	8.3
Dann	Benign	0.54

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: rs5030728; hg19: chr9-120474282; COSMIC: COSV62922754; COSMIC: COSV62922754;