4-186082920-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003265.3(TLR3):c.1234C>T(p.Leu412Phe) variant causes a missense change. The variant allele was found at a frequency of 0.284 in 1,613,766 control chromosomes in the GnomAD database, including 67,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L412V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.24 ( 5155 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62517 hom. )

Consequence

TLR3
NM_003265.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.10

Publications

454 publications found

Variant links:

Genes affected

TLR3 (HGNC:11849): (toll like receptor 3) 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 (PAMPs) 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. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of NF-kappaB and the production of type I interferons. It thus plays a role in host defense against multiple viruses. [provided by RefSeq, Jul 2021]

TLR3 Gene-Disease associations (from GenCC):

immunodeficiency 83, susceptibility to viral infections
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TLR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021493137).

BP6

Variant 4-186082920-C-T is Benign according to our data. Variant chr4-186082920-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.1234C>T	p.Leu412Phe	missense_variant	Exon 4 of 5	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8 link	c.1234C>T	p.Leu412Phe	missense_variant	Exon 4 of 5	1	NM_003265.3	ENSP00000296795.3

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35941

AN:

151972

Hom.:

5148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0691

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.321

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.282

GnomAD2 exomes

AF:

0.279

AC:

70051

AN:

250924

AF XY:

0.280

show subpopulations

Gnomad AFR exome

AF:

0.0647

Gnomad AMR exome

AF:

0.299

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.298

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.289

AC:

421977

AN:

1461676

Hom.:

62517

Cov.:

AF XY:

0.287

AC XY:

208939

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0604

AC:

2023

AN:

33480

American (AMR)

AF:

0.298

AC:

13331

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

6704

AN:

26132

East Asian (EAS)

AF:

0.299

AC:

11879

AN:

39698

South Asian (SAS)

AF:

0.240

AC:

20729

AN:

86232

European-Finnish (FIN)

AF:

0.323

AC:

17269

AN:

53394

Middle Eastern (MID)

AF:

0.247

AC:

1423

AN:

5766

European-Non Finnish (NFE)

AF:

0.298

AC:

331842

AN:

1111880

Other (OTH)

AF:

0.278

AC:

16777

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

18187

36373

54560

72746

90933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10832

21664

32496

43328

54160

<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:

0.236

AC:

35960

AN:

152090

Hom.:

5155

Cov.:

AF XY:

0.238

AC XY:

17727

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0691

AC:

2868

AN:

41530

American (AMR)

AF:

0.314

AC:

4793

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

863

AN:

3472

East Asian (EAS)

AF:

0.322

AC:

1664

AN:

5164

South Asian (SAS)

AF:

0.246

AC:

1184

AN:

4814

European-Finnish (FIN)

AF:

0.323

AC:

3411

AN:

10546

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.298

AC:

20272

AN:

67982

Other (OTH)

AF:

0.283

AC:

596

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1318

2635

3953

5270

6588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.276

Hom.:

27714

Bravo

AF:

0.227

TwinsUK

AF:

0.301

AC:

1117

ALSPAC

AF:

0.287

AC:

1105

ESP6500AA

AF:

0.0710

AC:

313

ESP6500EA

AF:

0.290

AC:

2496

ExAC

AF:

0.271

AC:

32913

Asia WGS

AF:

0.297

AC:

1036

AN:

3478

EpiCase

AF:

0.287

EpiControl

AF:

0.291

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 83, susceptibility to viral infections

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 25, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29290528, 24371259, 26298326, 31445170, 28046022, 23240626, 17434873, 18325643, 22549436, 18753640, 20413676, 20472559, 20855885, 21093032, 19016379, 21216866, 22174453, 22537752, 22504413, 21712495, 25304972, 22024499) -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF. Associated with susceptibility to infections, rheumatoid arthritis. Some functional evidence to show reduced IFN and TNF secretion in response to stimulation. This may be a risk allele, but unlikely to cause disease on its own -

Herpes simplex encephalitis, susceptibility to, 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TLR3-related disorder

Benign:1

Jan 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Susceptibility to HIV infection

Benign:1

Aug 08, 2018

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Susceptibility to HIV infection;C2751803:Immunodeficiency 83, susceptibility to viral infections

Benign:1

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;D;D

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-1.4

MutationAssessor

Pathogenic

4.1

H;.;.

PhyloP100

4.1

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.20

MPC

0.34

ClinPred

0.082

GERP RS

5.0

Varity_R

0.81

gMVP

0.57

Mutation Taster

=59/41

polymorphism (auto)

(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