NM_138554.5:c.260+546C>A

Variant names:

• chr9-117709275-C-A
• rs11536878
• NM_138554.5:c.260+546C>A

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+546C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0977 in 151,834 control chromosomes in the GnomAD database, including 827 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 0.098 (827 hom., cov: 32)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 22 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.260+546C>A		intron_variant	Intron 2 of 2	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.140+546C>A		intron_variant	Intron 3 of 3		NP_003257.1
TLR4	NM_138557.3	c.-340-3114C>A		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+546C>A		intron_variant	Intron 2 of 2	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+546C>A		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14794 AN: 151716 Hom.: 821 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.0977 AC: 14831 AN: 151834 Hom.: 827 Cov.: 32 AF XY: 0.0970 AC XY: 7196 AN XY: 74180

African (AFR) AF: 0.0436 AC: 1806 AN: 41392

American (AMR) AF: 0.157 AC: 2389 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3470

East Asian (EAS) AF: 0.132 AC: 681 AN: 5152

South Asian (SAS) AF: 0.130 AC: 622 AN: 4788

European-Finnish (FIN) AF: 0.0690 AC: 728 AN: 10550

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7748 AN: 67936

Other (OTH) AF: 0.105 AC: 222 AN: 2108

Alfa AF: 0.110 Hom.: 666

Bravo AF: 0.0995

Asia WGS AF: 0.125 AC: 435 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.14
DANN	Benign	0.54
PhyloP100		-1.3
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: rs11536878; hg19: chr9-120471553;