dbSNP rs7045953: TLR4:c.*8869A>G (chr9-117723517-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138554.5(TLR4):c.*8869A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,030 control chromosomes in the GnomAD database, including 3,165 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 0.19 ( 3165 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

TLR4
NM_138554.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0930

Publications

36 publications found

Variant links:

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]

TLR4 links:

ENSG00000285082 (HGNC:):

ENSG00000285082 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TLR4	NM_138554.5	MANE Select	c.*8869A>G	3_prime_UTR	Exon 3 of 3	NP_612564.1
TLR4	NM_003266.4		c.*8869A>G	3_prime_UTR	Exon 4 of 4	NP_003257.1
TLR4	NM_138557.3		c.*8869A>G	3_prime_UTR	Exon 2 of 2	NP_612567.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TLR4	ENST00000355622.8	TSL:1 MANE Select	c.*8869A>G	3_prime_UTR	Exon 3 of 3	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1		c.140+14788A>G	intron	N/A	ENSP00000513391.1
ENSG00000285082	ENST00000646089.2		c.93+18952A>G	intron	N/A	ENSP00000496197.1

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28790

AN:

151912

Hom.:

3155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.309

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.0898

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.170

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.190

AC:

28836

AN:

152030

Hom.:

3165

Cov.:

AF XY:

0.184

AC XY:

13667

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.309

AC:

12796

AN:

41422

American (AMR)

AF:

0.142

AC:

2166

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

797

AN:

3470

East Asian (EAS)

AF:

0.107

AC:

551

AN:

5166

South Asian (SAS)

AF:

0.121

AC:

586

AN:

4826

European-Finnish (FIN)

AF:

0.0898

AC:

949

AN:

10572

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10489

AN:

67986

Other (OTH)

AF:

0.174

AC:

368

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1169

2338

3507

4676

5845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.165

Hom.:

3948

Bravo

AF:

0.198

Asia WGS

AF:

0.141

AC:

492

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.72

(source)

DANN

Benign

0.24

PhyloP100

-0.093

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over