9-117710486-C-T

Variant names:

• chr9-117710486-C-T
• rs1927907
• NM_138554.5:c.260+1757C>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.260+1757C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 150,886 control chromosomes in the GnomAD database, including 2,659 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 0.18 (2659 hom., cov: 30)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 61 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.260+1757C>T		intron_variant	Intron 2 of 2	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.140+1757C>T		intron_variant	Intron 3 of 3		NP_003257.1
TLR4	NM_138557.3	c.-340-1903C>T		intron_variant	Intron 1 of 1		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.260+1757C>T		intron_variant	Intron 2 of 2	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+1757C>T		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 26880 AN: 150776 Hom.: 2660 Cov.: 30

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.178 AC: 26893 AN: 150886 Hom.: 2659 Cov.: 30 AF XY: 0.183 AC XY: 13485 AN XY: 73652

African (AFR) AF: 0.239 AC: 9789 AN: 40976

American (AMR) AF: 0.133 AC: 2013 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 532 AN: 3462

East Asian (EAS) AF: 0.221 AC: 1132 AN: 5126

South Asian (SAS) AF: 0.125 AC: 602 AN: 4806

European-Finnish (FIN) AF: 0.280 AC: 2881 AN: 10306

Middle Eastern (MID) AF: 0.155 AC: 45 AN: 290

European-Non Finnish (NFE) AF: 0.140 AC: 9456 AN: 67750

Other (OTH) AF: 0.158 AC: 330 AN: 2094

Alfa AF: 0.152 Hom.: 3065

Bravo AF: 0.172

Asia WGS AF: 0.155 AC: 538 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.51
DANN	Benign	0.50
PhyloP100		-0.53
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: rs1927907; hg19: chr9-120472764;