rs10759933

Variant names:

• chr9-117708094-A-C
• rs10759933
• NM_138554.5:c.94-469A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-117708094-A-C
• chr9-117708094-A-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.94-469A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0664 in 718,130 control chromosomes in the GnomAD database, including 1,919 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 0.081 (610 hom., cov: 32)
  • Exomes 𝑓: 0.063 (1309 hom.)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.94-469A>C		intron_variant	Intron 1 of 2	ENST00000355622.8	NP_612564.1
RNU6-1082P		n.117708094A>C		intragenic_variant
TLR4	NM_003266.4	c.-147-105A>C		intron_variant	Intron 1 of 3		NP_003257.1
TLR4	NM_138557.3	c.-341+3529A>C		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.94-469A>C		intron_variant	Intron 1 of 2	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.-147-105A>C		intron_variant	Intron 1 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.0806 AC: 12257 AN: 152138 Hom.: 612 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0719

GnomAD4 exome AF: 0.0626 AC: 35447 AN: 565874 Hom.: 1309 Cov.: 8 AF XY: 0.0624 AC XY: 16604 AN XY: 266284

African (AFR) AF: 0.143 AC: 1512 AN: 10582

American (AMR) AF: 0.0371 AC: 121 AN: 3262

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 192 AN: 3552

East Asian (EAS) AF: 0.00105 AC: 4 AN: 3808

South Asian (SAS) AF: 0.100 AC: 1299 AN: 12964

European-Finnish (FIN) AF: 0.0944 AC: 67 AN: 710

Middle Eastern (MID) AF: 0.0525 AC: 58 AN: 1104

European-Non Finnish (NFE) AF: 0.0603 AC: 30807 AN: 511240

Other (OTH) AF: 0.0744 AC: 1387 AN: 18652

GnomAD4 genome AF: 0.0806 AC: 12270 AN: 152256 Hom.: 610 Cov.: 32 AF XY: 0.0830 AC XY: 6178 AN XY: 74448

African (AFR) AF: 0.128 AC: 5313 AN: 41550

American (AMR) AF: 0.0533 AC: 815 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.115 AC: 554 AN: 4824

European-Finnish (FIN) AF: 0.0951 AC: 1009 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4226 AN: 68008

Other (OTH) AF: 0.0712 AC: 150 AN: 2108

Alfa AF: 0.0723 Hom.: 128

Bravo AF: 0.0761

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.64
PhyloP100		0.54
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: rs10759933; hg19: chr9-120470372;