rs7045953

Positions:

• chr9-117723517-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138554.5(TLR4):​c.*8869A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,030 control chromosomes in the GnomAD database, including 3,165 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 0.19 (3165 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930

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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.*8869A>G		3_prime_UTR_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.*8869A>G		3_prime_UTR_variant	4/4
TLR4	NM_138557.3	c.*8869A>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.*8869A>G		3_prime_UTR_variant	3/3	1	NM_138554.5	P1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28790 AN: 151912 Hom.: 3155 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0898

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.170

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.190 AC: 28836 AN: 152030 Hom.: 3165 Cov.: 32 AF XY: 0.184 AC XY: 13667 AN XY: 74324

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0898

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.174

Alfa AF: 0.161 Hom.: 2965

Bravo AF: 0.198

Asia WGS AF: 0.141 AC: 492 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	0.72
DANN	Benign	0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7045953; hg19: chr9-120485795;