rs5030721

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_138554.5(TLR4):c.1959G>A(p.Lys653Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,034 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

TLR4
NM_138554.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.391

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 9-117714087-G-A is Benign according to our data. Variant chr9-117714087-G-A is described in ClinVar as Benign. ClinVar VariationId is 786820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.391 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5 link	c.1959G>A	p.Lys653Lys	synonymous_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1	O00206-1
TLR4	NM_003266.4 link	c.1839G>A	p.Lys613Lys	synonymous_variant	Exon 4 of 4		NP_003257.1	O00206-2
TLR4	NM_138557.3 link	c.1359G>A	p.Lys453Lys	synonymous_variant	Exon 2 of 2		NP_612567.1	O00206-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 link	c.1959G>A	p.Lys653Lys	synonymous_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5		O00206-1
ENSG00000285082	ENST00000697666.1 link	c.140+5358G>A		intron_variant	Intron 3 of 4			ENSP00000513391.1		A0A8V8TMK6

Frequencies

GnomAD3 genomes

AF:

0.00829

AC:

1261

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00896

AC:

2248

AN:

250906

AF XY:

0.00960

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00640

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00867

GnomAD4 exome

AF:

0.0112

AC:

16403

AN:

1461776

Hom.:

110

Cov.:

AF XY:

0.0112

AC XY:

8174

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33476

American (AMR)

AF:

0.00626

AC:

280

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39688

South Asian (SAS)

AF:

0.0131

AC:

1129

AN:

86254

European-Finnish (FIN)

AF:

0.0142

AC:

759

AN:

53384

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0122

AC:

13548

AN:

1111986

Other (OTH)

AF:

0.00967

AC:

584

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1025

2050

3076

4101

5126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.00828

AC:

1261

AN:

152258

Hom.:

Cov.:

AF XY:

0.00873

AC XY:

650

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41546

American (AMR)

AF:

0.00686

AC:

105

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0118

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0187

AC:

198

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0118

AC:

806

AN:

68018

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

184

246

307

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:

0.00899

Hom.:

Bravo

AF:

0.00624

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0103

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TLR4: BP4, BP7, BS1, BS2 -

Aug 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.6

(source)

DANN

Benign

0.63

PhyloP100

0.39

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over