9-117715853-G-C

Variant names:

• chr9-117715853-G-C
• rs11536889
• NM_138554.5:c.*1205G>C

Variant summary

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

The NM_138554.5(TLR4):​c.*1205G>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 0.111 in 152,158 control chromosomes in the GnomAD database, including 1,203 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 0.11 (1203 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 234 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]

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 (EAS) allele frequency at 95% confidence interval = 0.242 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.*1205G>C		3_prime_UTR	Exon 3 of 3	NP_612564.1
	TLR4	NM_003266.4		c.*1205G>C		3_prime_UTR	Exon 4 of 4	NP_003257.1
	TLR4	NM_138557.3		c.*1205G>C		3_prime_UTR	Exon 2 of 2	NP_612567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.*1205G>C		3_prime_UTR	Exon 3 of 3	ENSP00000363089.5
	ENSG00000285082	ENST00000697666.1		c.140+7124G>C		intron	N/A	ENSP00000513391.1
	ENSG00000285082	ENST00000646089.2		c.93+11288G>C		intron	N/A	ENSP00000496197.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16930 AN: 152032 Hom.: 1204 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0897

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 1 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.111 AC: 16922 AN: 152150 Hom.: 1203 Cov.: 32 AF XY: 0.111 AC XY: 8251 AN XY: 74372

African (AFR) AF: 0.0299 AC: 1243 AN: 41534

American (AMR) AF: 0.121 AC: 1851 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.253 AC: 1309 AN: 5170

South Asian (SAS) AF: 0.175 AC: 841 AN: 4804

European-Finnish (FIN) AF: 0.0897 AC: 950 AN: 10588

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9982 AN: 67992

Other (OTH) AF: 0.107 AC: 226 AN: 2108

Alfa AF: 0.120 Hom.: 167

Bravo AF: 0.108

Asia WGS AF: 0.203 AC: 706 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.50
PhyloP100		-1.2
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: rs11536889; hg19: chr9-120478131; COSMIC: COSV62922315;