rs5030718

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_138554.5(TLR4):c.1420G>A(p.Glu474Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,926 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 22 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.547

Publications

21 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 Gene-Disease associations (from GenCC):

inflammatory bowel disease
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

TLR4 links:

ENSG00000285082 (HGNC:):

ENSG00000285082 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0030899942).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1686/152146) while in subpopulation AFR AF = 0.0385 (1598/41498). AF 95% confidence interval is 0.0369. There are 31 homozygotes in GnomAd4. There are 787 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR4	NM_138554.5	MANE Select	c.1420G>A	p.Glu474Lys	missense	Exon 3 of 3	NP_612564.1	O00206-1
TLR4	NM_003266.4		c.1300G>A	p.Glu434Lys	missense	Exon 4 of 4	NP_003257.1	O00206-2
TLR4	NM_138557.3		c.820G>A	p.Glu274Lys	missense	Exon 2 of 2	NP_612567.1	O00206-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR4	ENST00000355622.8	TSL:1 MANE Select	c.1420G>A	p.Glu474Lys	missense	Exon 3 of 3	ENSP00000363089.5	O00206-1
TLR4	ENST00000394487.5	TSL:1	c.1300G>A	p.Glu434Lys	missense	Exon 4 of 4	ENSP00000377997.4	O00206-2
TLR4	ENST00000472304.2	TSL:1	c.*1154G>A		3_prime_UTR	Exon 2 of 2	ENSP00000496429.1	A0A2R8Y7P4

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1685

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00309

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00308

AC:

773

AN:

250658

AF XY:

0.00224

show subpopulations

Gnomad AFR exome

AF:

0.0397

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00277

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00118

AC:

1729

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

774

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0380

AC:

1271

AN:

33478

American (AMR)

AF:

0.00183

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00262

AC:

104

AN:

39690

South Asian (SAS)

AF:

0.000162

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000899

AC:

100

AN:

1111972

Other (OTH)

AF:

0.00240

AC:

145

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0111

AC:

1686

AN:

152146

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

787

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0385

AC:

1598

AN:

41498

American (AMR)

AF:

0.00268

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00309

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68018

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

165

248

330

413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00433

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0402

AC:

177

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00380

AC:

461

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.13

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.081

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

PhyloP100

-0.55

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.26

REVEL

Benign

0.042

Sift

Benign

0.37

Sift4G

Benign

0.67

Polyphen

0.0010

Vest4

0.046

MVP

0.45

MPC

0.096

ClinPred

0.0090

GERP RS

-10

Varity_R

0.15

gMVP

0.20

Mutation Taster

=82/18

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over