rs1927905

Positions:

• chr9-117723030-T-C

Variant summary

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

The NM_138554.5(TLR4):​c.*8382T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 152,150 control chromosomes in the GnomAD database, including 1,197 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 0.099 (1197 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: -2.01

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.*8382T>C		3_prime_UTR_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.*8382T>C		3_prime_UTR_variant	4/4
TLR4	NM_138557.3	c.*8382T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.*8382T>C		3_prime_UTR_variant	3/3	1	NM_138554.5	P1

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14977 AN: 152032 Hom.: 1195 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0978

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0904

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

Gnomad4 AMR exome AF: 0.00

GnomAD4 genome AF: 0.0986 AC: 15005 AN: 152150 Hom.: 1197 Cov.: 32 AF XY: 0.0957 AC XY: 7118 AN XY: 74402

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.0772

Gnomad4 ASJ AF: 0.0978

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0498

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0511

Gnomad4 OTH AF: 0.0942

Alfa AF: 0.0638 Hom.: 240

Bravo AF: 0.108

Asia WGS AF: 0.0510 AC: 178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0060
DANN	Benign	0.20

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1927905; hg19: chr9-120485308;