4-186083063-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003265.3(TLR3):c.1377C>T(p.Phe459Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,800 control chromosomes in the GnomAD database, including 74,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 5962 hom., cov: 32)

Exomes 𝑓: 0.30 ( 68766 hom. )

Consequence

TLR3
NM_003265.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.944

Publications

133 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 4-186083063-C-T is Benign according to our data. Variant chr4-186083063-C-T is described in ClinVar as Benign. ClinVar VariationId is 403543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.944 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.1377C>T	p.Phe459Phe	synonymous_variant	Exon 4 of 5	ENST00000296795.8	NP_003256.1	O15455-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8 link	c.1377C>T	p.Phe459Phe	synonymous_variant	Exon 4 of 5	1	NM_003265.3	ENSP00000296795.3		O15455-1

Frequencies

GnomAD3 genomes

AF:

0.275

AC:

41804

AN:

151866

Hom.:

5963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.336

Gnomad SAS

AF:

0.324

Gnomad FIN

AF:

0.288

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.270

GnomAD2 exomes

AF:

0.302

AC:

75834

AN:

251196

AF XY:

0.302

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.323

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.305

AC:

445532

AN:

1461816

Hom.:

68766

Cov.:

AF XY:

0.305

AC XY:

221921

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.196

AC:

6578

AN:

33478

American (AMR)

AF:

0.342

AC:

15275

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6202

AN:

26136

East Asian (EAS)

AF:

0.356

AC:

14137

AN:

39700

South Asian (SAS)

AF:

0.321

AC:

27671

AN:

86246

European-Finnish (FIN)

AF:

0.292

AC:

15595

AN:

53408

Middle Eastern (MID)

AF:

0.285

AC:

1645

AN:

5768

European-Non Finnish (NFE)

AF:

0.306

AC:

340150

AN:

1111964

Other (OTH)

AF:

0.303

AC:

18279

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

20648

41295

61943

82590

103238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11246

22492

33738

44984

56230

<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:

0.275

AC:

41827

AN:

151984

Hom.:

5962

Cov.:

AF XY:

0.278

AC XY:

20641

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.199

AC:

8236

AN:

41472

American (AMR)

AF:

0.304

AC:

4639

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

822

AN:

3468

East Asian (EAS)

AF:

0.335

AC:

1728

AN:

5156

South Asian (SAS)

AF:

0.323

AC:

1551

AN:

4804

European-Finnish (FIN)

AF:

0.288

AC:

3034

AN:

10552

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20822

AN:

67938

Other (OTH)

AF:

0.271

AC:

571

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1551

3102

4652

6203

7754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.153

Hom.:

10605

Bravo

AF:

0.274

Asia WGS

AF:

0.311

AC:

1079

AN:

3478

EpiCase

AF:

0.306

EpiControl

AF:

0.301

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Oct 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. -

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 -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.9

(source)

DANN

Benign

0.59

PhyloP100

0.94

Mutation Taster

=100/0

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