rs7037117

chr9-117721385-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.*6737A>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 0.392 in 152,284 control chromosomes in the GnomAD database, including 14,941 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 0.39 (14941 hom., cov: 33)
  • Exomes 𝑓: 0.19 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.972

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.*6737A>G		3_prime_UTR_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.*6737A>G		3_prime_UTR_variant	4/4
TLR4	NM_138557.3	c.*6737A>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.*6737A>G		3_prime_UTR_variant	3/3	1	NM_138554.5	P1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59492 AN: 151994 Hom.: 14904 Cov.: 33

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.192 AC: 33 AN: 172 Hom.: 0 Cov.: 0 AF XY: 0.179 AC XY: 14 AN XY: 78

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.0667

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.0833

GnomAD4 genome AF: 0.392 AC: 59596 AN: 152112 Hom.: 14941 Cov.: 33 AF XY: 0.389 AC XY: 28959 AN XY: 74362

Gnomad4 AFR AF: 0.721

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.340

Alfa AF: 0.318 Hom.: 1977

Bravo AF: 0.406

Asia WGS AF: 0.314 AC: 1089 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.47
Dann	Benign	0.51

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7037117; hg19: chr9-120483663;