chr9-117715754-C-T

Position:

• chr9-117715754-C-T

Variant summary

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

The ENST00000355622.8(TLR4):​c.*1106C>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 0.097 in 152,194 control chromosomes in the GnomAD database, including 1,480 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 0.097 (1480 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TLR4 ENST00000355622.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.991

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*1106C>T		3_prime_UTR_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*1106C>T		3_prime_UTR_variant	4/4		NP_003257.1
TLR4	NM_138557.3	c.*1106C>T		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.*1106C>T		3_prime_UTR_variant	3/3	1	NM_138554.5	ENSP00000363089	P1
TLR4	ENST00000394487.5	c.*1106C>T		3_prime_UTR_variant	4/4	1		ENSP00000377997

Frequencies

GnomAD3 genomes AF: 0.0969 AC: 14731 AN: 152078 Hom.: 1474 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0761

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0970 AC: 14764 AN: 152194 Hom.: 1480 Cov.: 32 AF XY: 0.0956 AC XY: 7116 AN XY: 74410

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.0456

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.0432

Gnomad4 SAS AF: 0.0696

Gnomad4 FIN AF: 0.0446

Gnomad4 NFE AF: 0.0300

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.0599 Hom.: 277

Bravo AF: 0.104

Asia WGS AF: 0.0670 AC: 234 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.86
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7869402; hg19: chr9-120478032; COSMIC: COSV62923104; COSMIC: COSV62923104;