ENST00000394487.5:c.-126A>C

Variant names:

• chr9-117708220-A-C
• rs11536871
• ENST00000394487.5:c.-126A>C

Variant summary

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

The ENST00000394487.5(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 ENST00000394487.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.540
• Publications: 11 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=-0.85).
• 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 passed 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

African (AFR) AF: 0.00618 AC: 123 AN: 19894

American (AMR) AF: 0.0302 AC: 194 AN: 6414

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 715 AN: 8016

East Asian (EAS) AF: 0.000299 AC: 3 AN: 10046

South Asian (SAS) AF: 0.0113 AC: 344 AN: 30408

European-Finnish (FIN) AF: 0.0123 AC: 58 AN: 4702

Middle Eastern (MID) AF: 0.0508 AC: 103 AN: 2026

European-Non Finnish (NFE) AF: 0.0380 AC: 31309 AN: 823532

Other (OTH) 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

African (AFR) AF: 0.00669 AC: 278 AN: 41568

American (AMR) AF: 0.0286 AC: 437 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4820

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10622

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2568 AN: 68016

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

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
PhyloP100		0.54
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

Other links and lift over

dbSNP: rs11536871; hg19: chr9-120470498;