9-117718534-T-C

Position:

• chr9-117718534-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.*3886T>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 0.374 in 151,840 control chromosomes in the GnomAD database, including 14,102 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 0.37 (14102 hom., cov: 31)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.808

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 = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*3886T>C		3_prime_UTR_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*3886T>C		3_prime_UTR_variant	4/4		NP_003257.1
TLR4	NM_138557.3	c.*3886T>C		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.*3886T>C		3_prime_UTR_variant	3/3	1	NM_138554.5	ENSP00000363089	P1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56715 AN: 151716 Hom.: 14062 Cov.: 31

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.333

GnomAD4 genome AF: 0.374 AC: 56819 AN: 151834 Hom.: 14102 Cov.: 31 AF XY: 0.369 AC XY: 27384 AN XY: 74198

Gnomad4 AFR AF: 0.714

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.324

Alfa AF: 0.265 Hom.: 11572

Bravo AF: 0.385

Asia WGS AF: 0.279 AC: 968 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	0.83
DANN	Benign	0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554973; hg19: chr9-120480812;