rs5030728

Variant names:

• chr9-117712004-G-A
• rs5030728
• NM_138554.5:c.261-385G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-117712004-G-A
• chr9-117712004-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 80 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]

TLR4 Gene-Disease associations (from GenCC):

• inflammatory bowel disease

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.261-385G>A		intron	N/A	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.141-385G>A		intron	N/A	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.-340-385G>A		intron	N/A	NP_612567.1	O00206-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.261-385G>A		intron	N/A	ENSP00000363089.5	O00206-1
	TLR4	ENST00000394487.5	TSL:1	c.141-385G>A		intron	N/A	ENSP00000377997.4	O00206-2
	ENSG00000285082	ENST00000697666.1		c.140+3275G>A		intron	N/A	ENSP00000513391.1	A0A8V8TMK6

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

African (AFR) AF: 0.140 AC: 5803 AN: 41510

American (AMR) AF: 0.233 AC: 3557 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 847 AN: 3464

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5178

South Asian (SAS) AF: 0.220 AC: 1061 AN: 4820

European-Finnish (FIN) AF: 0.239 AC: 2527 AN: 10580

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20333 AN: 67984

Other (OTH) AF: 0.246 AC: 521 AN: 2114

Alfa AF: 0.275 Hom.: 9304

Bravo AF: 0.227

Asia WGS AF: 0.102 AC: 359 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.3
DANN	Benign	0.54
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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