9-117715853-G-C

Variant names:

• chr9-117715853-G-C
• rs11536889
• NM_138554.5:c.*1205G>C

Variant summary

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

The NM_138554.5(TLR4):​c.*1205G>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 0.111 in 152,158 control chromosomes in the GnomAD database, including 1,203 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 0.11 (1203 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24

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]

ENSG00000285082 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*1205G>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*1205G>C		3_prime_UTR_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3	c.*1205G>C		3_prime_UTR_variant	Exon 2 of 2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.*1205G>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+7124G>C		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16930 AN: 152032 Hom.: 1204 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0897

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.111 AC: 16922 AN: 152150 Hom.: 1203 Cov.: 32 AF XY: 0.111 AC XY: 8251 AN XY: 74372

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.0897

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.107

Alfa AF: 0.120 Hom.: 167

Bravo AF: 0.108

Asia WGS AF: 0.203 AC: 706 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.50

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: rs11536889; hg19: chr9-120478131; COSMIC: COSV62922315; COSMIC: COSV62922315;