rs913930

Positions:

• chr9-117721731-G-A
• chr9-117721731-G-C

Variant summary

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

The NM_138554.5(TLR4):​c.*7083G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 152,116 control chromosomes in the GnomAD database, including 41,391 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 0.73 (41391 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.623

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*7083G>A		3_prime_UTR_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*7083G>A		3_prime_UTR_variant	4/4		NP_003257.1
TLR4	NM_138557.3	c.*7083G>A		3_prime_UTR_variant	2/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.*7083G>A		3_prime_UTR_variant	3/3	1	NM_138554.5	ENSP00000363089	P1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110716 AN: 151998 Hom.: 41321 Cov.: 33

Gnomad AFR AF: 0.868

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.707

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: 0.729 AC: 110847 AN: 152116 Hom.: 41391 Cov.: 33 AF XY: 0.730 AC XY: 54259 AN XY: 74346

Gnomad4 AFR AF: 0.868

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.687

Gnomad4 EAS AF: 0.987

Gnomad4 SAS AF: 0.772

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.646

Gnomad4 OTH AF: 0.710

Alfa AF: 0.667 Hom.: 45478

Bravo AF: 0.742

Asia WGS AF: 0.884 AC: 3071 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.4
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs913930; hg19: chr9-120484009;