rs7860896

Variant names:

• chr9-117720825-A-G
• rs7860896
• NM_138554.5:c.*6177A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138554.5(TLR4):​c.*6177A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,214 control chromosomes in the GnomAD database, including 4,227 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 0.19 (4224 hom., cov: 32)
  • Exomes 𝑓: 0.074 (3 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 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.*6177A>G		3_prime_UTR	Exon 3 of 3	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.*6177A>G		3_prime_UTR	Exon 4 of 4	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.*6177A>G		3_prime_UTR	Exon 2 of 2	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.*6177A>G		3_prime_UTR	Exon 3 of 3	ENSP00000363089.5	O00206-1
	ENSG00000285082	ENST00000697666.1		c.140+12096A>G		intron	N/A	ENSP00000513391.1	A0A8V8TMK6
	ENSG00000285082	ENST00000646089.2		c.93+16260A>G		intron	N/A	ENSP00000496197.1	A0A2R8YGN2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28474 AN: 151826 Hom.: 4213 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0954

Gnomad OTH AF: 0.154

GnomAD4 exome AF: 0.0741 AC: 20 AN: 270 Hom.: 3 Cov.: 0 AF XY: 0.0885 AC XY: 17 AN XY: 192

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.167 AC: 1 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.0676 AC: 15 AN: 222

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.188 AC: 28533 AN: 151944 Hom.: 4224 Cov.: 32 AF XY: 0.188 AC XY: 13998 AN XY: 74288

African (AFR) AF: 0.416 AC: 17231 AN: 41396

American (AMR) AF: 0.101 AC: 1540 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 289 AN: 3472

East Asian (EAS) AF: 0.0444 AC: 229 AN: 5160

South Asian (SAS) AF: 0.180 AC: 868 AN: 4814

European-Finnish (FIN) AF: 0.140 AC: 1483 AN: 10572

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0954 AC: 6480 AN: 67950

Other (OTH) AF: 0.153 AC: 324 AN: 2112

Alfa AF: 0.159 Hom.: 723

Bravo AF: 0.191

Asia WGS AF: 0.138 AC: 479 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.43
PhyloP100		-0.0030

Splicing

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

Other links and lift over

dbSNP: rs7860896; hg19: chr9-120483103;