rs11536871

Variant names:

• chr9-117708220-A-C
• rs11536871
• ENST00000394487:c.-126A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003266.4(TLR4):​c.-126A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 1,090,370 control chromosomes in the GnomAD database, including 755 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 0.025 (82 hom., cov: 32)
  • Exomes 𝑓: 0.036 (673 hom.)
• Consequence: TLR4 NM_003266.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.540

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=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0252 (3840/152300) while in subpopulation NFE AF = 0.0378 (2568/68016). AF 95% confidence interval is 0.0365. There are 82 homozygotes in GnomAd4. There are 1704 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 82 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.94-343A>C		intron_variant	Intron 1 of 2	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.-126A>C		5_prime_UTR_variant	Exon 2 of 4		NP_003257.1
TLR4	NM_138557.3	c.-341+3655A>C		intron_variant	Intron 1 of 1		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285082	ENST00000697666.1	c.-126A>C		5_prime_UTR_variant	Exon 2 of 5			ENSP00000513391.1
TLR4	ENST00000355622.8	c.94-343A>C		intron_variant	Intron 1 of 2	1	NM_138554.5	ENSP00000363089.5

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3845 AN: 152182 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0339

GnomAD4 exome AF: 0.0363 AC: 34042 AN: 938070 Hom.: 673 Cov.: 30 AF XY: 0.0359 AC XY: 15808 AN XY: 439860

Gnomad4 AFR exome AF: 0.00618 AC: 123 AN: 19894

Gnomad4 AMR exome AF: 0.0302 AC: 194 AN: 6414

Gnomad4 ASJ exome AF: 0.0892 AC: 715 AN: 8016

Gnomad4 EAS exome AF: 0.000299 AC: 3 AN: 10046

Gnomad4 SAS exome AF: 0.0113 AC: 344 AN: 30408

Gnomad4 FIN exome AF: 0.0123 AC: 58 AN: 4702

Gnomad4 NFE exome AF: 0.0380 AC: 31309 AN: 823532

Gnomad4 Remaining exome AF: 0.0361 AC: 1193 AN: 33032

GnomAD4 genome AF: 0.0252 AC: 3840 AN: 152300 Hom.: 82 Cov.: 32 AF XY: 0.0229 AC XY: 1704 AN XY: 74472

Gnomad4 AFR AF: 0.00669 AC: 0.00668784 AN: 0.00668784

Gnomad4 AMR AF: 0.0286 AC: 0.0285733 AN: 0.0285733

Gnomad4 ASJ AF: 0.0867 AC: 0.0866935 AN: 0.0866935

Gnomad4 EAS AF: 0.000193 AC: 0.000192753 AN: 0.000192753

Gnomad4 SAS AF: 0.0108 AC: 0.0107884 AN: 0.0107884

Gnomad4 FIN AF: 0.0106 AC: 0.0106383 AN: 0.0106383

Gnomad4 NFE AF: 0.0378 AC: 0.0377558 AN: 0.0377558

Gnomad4 OTH AF: 0.0331 AC: 0.0331126 AN: 0.0331126

Alfa AF: 0.0291 Hom.: 23

Bravo AF: 0.0268

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.46
Mutation Taster		=100/0	polymorphism

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: rs11536871; hg19: chr9-120470498;