Genetic Variant TLR4:c.*7083G>A (chr9-117721731-G-A) – 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.*7083G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 152,116 control chromosomes in the GnomAD database, including 41,391 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 0.73 ( 41391 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

TLR4
NM_138554.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.623

Publications

33 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=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 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.*7083G>A	3_prime_UTR	Exon 3 of 3	NP_612564.1
TLR4	NM_003266.4		c.*7083G>A	3_prime_UTR	Exon 4 of 4	NP_003257.1
TLR4	NM_138557.3		c.*7083G>A	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.*7083G>A	3_prime_UTR	Exon 3 of 3	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1		c.140+13002G>A	intron	N/A	ENSP00000513391.1
ENSG00000285082	ENST00000646089.2		c.93+17166G>A	intron	N/A	ENSP00000496197.1

Frequencies

GnomAD3 genomes

AF:

0.728

AC:

110716

AN:

151998

Hom.:

41321

Cov.:

show subpopulations

Gnomad AFR

AF:

0.868

Gnomad AMI

AF:

0.616

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.687

Gnomad EAS

AF:

0.987

Gnomad SAS

AF:

0.772

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.646

Gnomad OTH

AF:

0.707

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:

0.729

AC:

110847

AN:

152116

Hom.:

41391

Cov.:

AF XY:

0.730

AC XY:

54259

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.868

AC:

36086

AN:

41550

American (AMR)

AF:

0.728

AC:

11117

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.687

AC:

2386

AN:

3472

East Asian (EAS)

AF:

0.987

AC:

5122

AN:

5188

South Asian (SAS)

AF:

0.772

AC:

3720

AN:

4818

European-Finnish (FIN)

AF:

0.594

AC:

6259

AN:

10538

Middle Eastern (MID)

AF:

0.596

AC:

174

AN:

292

European-Non Finnish (NFE)

AF:

0.646

AC:

43924

AN:

67966

Other (OTH)

AF:

0.710

AC:

1497

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1471

2942

4413

5884

7355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.672

Hom.:

62821

Bravo

AF:

0.742

Asia WGS

AF:

0.884

AC:

3071

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

5.4

(source)

DANN

Benign

0.62

PhyloP100

0.62

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