9-117712651-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138554.5(TLR4):c.523A>G(p.Thr175Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,613,610 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 6 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0210

Publications

16 publications found

Variant links:

COSMIC-nc: COSV105915035

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062856674).

BP6

Variant 9-117712651-A-G is Benign according to our data. Variant chr9-117712651-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3033547.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 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.523A>G	p.Thr175Ala	missense	Exon 3 of 3	NP_612564.1	O00206-1
TLR4	NM_003266.4		c.403A>G	p.Thr135Ala	missense	Exon 4 of 4	NP_003257.1	O00206-2
TLR4	NM_138557.3		c.-78A>G		5_prime_UTR	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.523A>G	p.Thr175Ala	missense	Exon 3 of 3	ENSP00000363089.5	O00206-1
TLR4	ENST00000394487.5	TSL:1	c.403A>G	p.Thr135Ala	missense	Exon 4 of 4	ENSP00000377997.4	O00206-2
TLR4	ENST00000472304.2	TSL:1	c.*257A>G		3_prime_UTR	Exon 2 of 2	ENSP00000496429.1	A0A2R8Y7P4

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000651

AC:

163

AN:

250362

AF XY:

0.000665

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.00301

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000517

AC:

755

AN:

1461362

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

374

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0104

AC:

411

AN:

39686

South Asian (SAS)

AF:

0.000373

AC:

AN:

85844

European-Finnish (FIN)

AF:

0.00260

AC:

139

AN:

53402

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000128

AC:

142

AN:

1111972

Other (OTH)

AF:

0.000447

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000493

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41568

American (AMR)

AF:

0.000327

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00484

AC:

AN:

5170

South Asian (SAS)

AF:

0.000832

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000439

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TLR4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.15

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.063

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PhyloP100

-0.021

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.95

REVEL

Benign

0.042

Sift

Benign

0.16

Sift4G

Benign

0.26

Polyphen

0.019

Vest4

0.082

MVP

0.28

MPC

0.089

ClinPred

0.014

GERP RS

-7.9

Varity_R

0.090

gMVP

0.12

Mutation Taster

=98/2

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