9-117716658-G-C

Position:

• chr9-117716658-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138554.5(TLR4):​c.*2010G>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 0.161 in 152,100 control chromosomes in the GnomAD database, including 2,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2074 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.719

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 9-117716658-G-C is Benign according to our data. Variant chr9-117716658-G-C is described in ClinVar as [Benign]. Clinvar id is 1276780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*2010G>C		3_prime_UTR_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*2010G>C		3_prime_UTR_variant	4/4		NP_003257.1
TLR4	NM_138557.3	c.*2010G>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.*2010G>C		3_prime_UTR_variant	3/3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+7929G>C		intron_variant				ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24422 AN: 151982 Hom.: 2065 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0908

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.151

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.161 AC: 24462 AN: 152100 Hom.: 2074 Cov.: 32 AF XY: 0.156 AC XY: 11626 AN XY: 74360

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0908

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.155

Alfa AF: 0.0573 Hom.: 69

Bravo AF: 0.165

Asia WGS AF: 0.126 AC: 438 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 31785408) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.47
DANN	Benign	0.42

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: rs7873784; hg19: chr9-120478936;