9-117708606-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_138554.5(TLR4):c.137A>G(p.Tyr46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,613,938 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 12 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.557

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075338185).

BP6

Variant 9-117708606-A-G is Benign according to our data. Variant chr9-117708606-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3250546.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-117708606-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5 link	c.137A>G	p.Tyr46Cys	missense_variant	Exon 2 of 3	ENST00000355622.8	NP_612564.1	O00206-1
TLR4	NM_003266.4 link	c.17A>G	p.Tyr6Cys	missense_variant	Exon 3 of 4		NP_003257.1	O00206-2
TLR4	NM_138557.3 link	c.-340-3783A>G		intron_variant	Intron 1 of 1		NP_612567.1	O00206-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 link	c.137A>G	p.Tyr46Cys	missense_variant	Exon 2 of 3	1	NM_138554.5	ENSP00000363089.5		O00206-1
ENSG00000285082	ENST00000697666.1 link	c.17A>G	p.Tyr6Cys	missense_variant	Exon 3 of 5			ENSP00000513391.1		A0A8V8TMK6

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00241

AC:

605

AN:

251224

Hom.:

AF XY:

0.00234

AC XY:

317

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00425

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00319

AC:

4668

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

2231

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00380

Gnomad4 OTH exome

AF:

0.00354

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152278

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00381

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00373

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ENSG00000285082: BP4, BS2; TLR4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;T

Eigen

Benign

-0.0018

Eigen_PC

Benign

-0.048

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.93

D;.;D

M_CAP

Benign

0.0097

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;M;M

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.047

D;.;D

Sift4G

Benign

0.12

T;.;T

Polyphen

0.98

.;D;D

Vest4

0.26

MVP

0.85

MPC

0.38

ClinPred

0.026

GERP RS

-0.28

Varity_R

0.60

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over