9-117707554-A-G

Position:

• chr9-117707554-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_138554.5(TLR4):​c.94-1009A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 152,334 control chromosomes in the GnomAD database, including 66 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 0.023 (66 hom., cov: 33)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0229 (3496/152334) while in subpopulation NFE AF= 0.0355 (2414/68028). AF 95% confidence interval is 0.0343. There are 66 homozygotes in gnomad4. There are 1537 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 66 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.94-1009A>G		intron_variant		ENST00000355622.8
TLR4	NM_003266.4	c.-147-645A>G		intron_variant
TLR4	NM_138557.3	c.-341+2989A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.94-1009A>G		intron_variant		1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.-147-645A>G		intron_variant		1
TLR4	ENST00000472304.2	c.93+2989A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3500 AN: 152216 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0277

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

GnomAD4 genome AF: 0.0229 AC: 3496 AN: 152334 Hom.: 66 Cov.: 33 AF XY: 0.0206 AC XY: 1537 AN XY: 74494

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0533

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00827

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0355

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0349 Hom.: 138

Bravo AF: 0.0243

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs11536869; hg19: chr9-120469832;