rs7856729

chr9-117719578-G-T

Variant summary

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

The NM_138554.5(TLR4):c.*4930G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,082 control chromosomes in the GnomAD database, including 3,010 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 (3010 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.*4930G>T		3_prime_UTR_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.*4930G>T		3_prime_UTR_variant	4/4
TLR4	NM_138557.3	c.*4930G>T		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.*4930G>T		3_prime_UTR_variant	3/3	1	NM_138554.5	P1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28296 AN: 151964 Hom.: 3002 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0898

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.166

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.186 AC: 28338 AN: 152082 Hom.: 3010 Cov.: 32 AF XY: 0.180 AC XY: 13420 AN XY: 74350

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0898

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.170

Alfa AF: 0.161 Hom.: 1729

Bravo AF: 0.194

Asia WGS AF: 0.130 AC: 453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.076
Dann	Benign	0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7856729; hg19: chr9-120481856;