Genetic Variant TLR4:c.260+1723T>C (chr9-117710452-T-C) – 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.260+1723T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 136,222 control chromosomes in the GnomAD database, including 8,253 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 0.34 ( 8253 hom., cov: 29)

Consequence

TLR4
NM_138554.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.54

Publications

56 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=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TLR4	NM_138554.5 link	c.260+1723T>C	intron_variant	Intron 2 of 2	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 link	c.140+1723T>C	intron_variant	Intron 3 of 3		NP_003257.1
TLR4	NM_138557.3 link	c.-340-1937T>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 link	c.260+1723T>C		intron_variant	Intron 2 of 2	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1 link	c.140+1723T>C		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

45848

AN:

136188

Hom.:

8261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.417

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.617

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.375

Gnomad MID

AF:

0.374

Gnomad NFE

AF:

0.412

Gnomad OTH

AF:

0.378

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.337

AC:

45842

AN:

136222

Hom.:

8253

Cov.:

AF XY:

0.341

AC XY:

22555

AN XY:

66138

show subpopulations

African (AFR)

AF:

0.115

AC:

4359

AN:

37820

American (AMR)

AF:

0.418

AC:

5816

AN:

13924

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

1325

AN:

3204

East Asian (EAS)

AF:

0.617

AC:

3117

AN:

5050

South Asian (SAS)

AF:

0.458

AC:

1883

AN:

4114

European-Finnish (FIN)

AF:

0.375

AC:

3126

AN:

8330

Middle Eastern (MID)

AF:

0.389

AC:

105

AN:

270

European-Non Finnish (NFE)

AF:

0.412

AC:

25016

AN:

60730

Other (OTH)

AF:

0.378

AC:

711

AN:

1882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1467

2934

4400

5867

7334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.241

Hom.:

1731

Bravo

AF:

0.305

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.77

(source)

DANN

Benign

0.47

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over