Variant 9-117712970-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138554.5(TLR4):c.842G>A(p.Cys281Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00288 in 1,614,074 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 5 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 5.36

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024662405).

BS2

High Homozygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TLR4	NM_138554.5 linkuse as main transcript	c.842G>A	p.Cys281Tyr	missense_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 linkuse as main transcript	c.722G>A	p.Cys241Tyr	missense_variant	4/4		NP_003257.1
TLR4	NM_138557.3 linkuse as main transcript	c.242G>A	p.Cys81Tyr	missense_variant	2/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 linkuse as main transcript	c.842G>A	p.Cys281Tyr	missense_variant	3/3	1	NM_138554.5	ENSP00000363089	P1	O00206-1
TLR4	ENST00000394487.5 linkuse as main transcript	c.722G>A	p.Cys241Tyr	missense_variant	4/4	1		ENSP00000377997		O00206-2
TLR4	ENST00000472304.2 linkuse as main transcript	c.*576G>A		3_prime_UTR_variant	2/2	1		ENSP00000496429

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

348

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00230

AC:

576

AN:

250924

Hom.:

AF XY:

0.00239

AC XY:

324

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00317

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00294

AC:

4303

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2175

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00356

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00199

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00336

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00228

AC:

347

AN:

152302

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00382

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00334

Hom.:

Bravo

AF:

0.00263

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00208

AC:

252

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00387

EpiControl

AF:

0.00379

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

not provided, no classification provided

literature only

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.42

.;T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;.;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.8

.;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.4

D;.;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.0080

D;.;D

Polyphen

1.0

.;D;D

Vest4

0.82

MVP

0.90

MPC

0.57

ClinPred

0.078

GERP RS

4.9

Varity_R

0.93

gMVP

0.70

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

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