9-117707776-A-G

Variant names:

• chr9-117707776-A-G
• rs1927911
• NM_138554.5:c.94-787A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138554.5(TLR4):​c.94-787A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,116 control chromosomes in the GnomAD database, including 31,482 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 0.62 (31482 hom., cov: 33)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 205 publications found

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:):

RNU6-1082P (HGNC:48045): (RNA, U6 small nuclear 1082, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.94-787A>G		intron_variant	Intron 1 of 2	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.-147-423A>G		intron_variant	Intron 1 of 3		NP_003257.1
TLR4	NM_138557.3	c.-341+3211A>G		intron_variant	Intron 1 of 1		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.94-787A>G		intron_variant	Intron 1 of 2	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.-147-423A>G		intron_variant	Intron 1 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94886 AN: 151998 Hom.: 31490 Cov.: 33

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.670

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.624 AC: 94907 AN: 152116 Hom.: 31482 Cov.: 33 AF XY: 0.624 AC XY: 46411 AN XY: 74360

African (AFR) AF: 0.376 AC: 15598 AN: 41494

American (AMR) AF: 0.676 AC: 10321 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2369 AN: 3472

East Asian (EAS) AF: 0.622 AC: 3214 AN: 5170

South Asian (SAS) AF: 0.742 AC: 3582 AN: 4828

European-Finnish (FIN) AF: 0.652 AC: 6887 AN: 10562

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50591 AN: 67992

Other (OTH) AF: 0.666 AC: 1410 AN: 2116

Alfa AF: 0.710 Hom.: 52560

Bravo AF: 0.615

Asia WGS AF: 0.673 AC: 2342 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.55
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1927911; hg19: chr9-120470054;