rs5030729

Variant names:

• chr9-117712061-A-G
• rs5030729
• NM_138554.5:c.261-328A>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.261-328A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 152,272 control chromosomes in the GnomAD database, including 345 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 0.037 (345 hom., cov: 32)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.928
• Publications: 6 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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.261-328A>G		intron	N/A	NP_612564.1
	TLR4	NM_003266.4		c.141-328A>G		intron	N/A	NP_003257.1
	TLR4	NM_138557.3		c.-340-328A>G		intron	N/A	NP_612567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.261-328A>G		intron	N/A	ENSP00000363089.5
	TLR4	ENST00000394487.5	TSL:1	c.141-328A>G		intron	N/A	ENSP00000377997.4
	ENSG00000285082	ENST00000697666.1		c.140+3332A>G		intron	N/A	ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5570 AN: 152154 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0225

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

GnomAD4 genome AF: 0.0367 AC: 5581 AN: 152272 Hom.: 345 Cov.: 32 AF XY: 0.0358 AC XY: 2668 AN XY: 74462

African (AFR) AF: 0.126 AC: 5234 AN: 41536

American (AMR) AF: 0.0147 AC: 225 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68028

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0253 Hom.: 56

Bravo AF: 0.0410

Asia WGS AF: 0.00895 AC: 31 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.81
PhyloP100		0.93
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: rs5030729; hg19: chr9-120474339;