4-186082310-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000512264.1(TLR3):c.-208C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,476,906 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

TLR3
ENST00000512264.1 5_prime_UTR

Scores

Splicing: ADA: 0.0004339

Clinical Significance

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

Conservation

PhyloP100: -0.359

Publications

2 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 4-186082310-C-A is Benign according to our data. Variant chr4-186082310-C-A is described in ClinVar as Benign. ClinVar VariationId is 537923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.634-10C>A		intron_variant	Intron 3 of 4	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.634-10C>A		intron_variant	Intron 3 of 4	1	NM_003265.3	ENSP00000296795.3		O15455-1

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

341

AN:

140980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00330

Gnomad ASJ

AF:

0.0183

Gnomad EAS

AF:

0.000222

Gnomad SAS

AF:

0.000702

Gnomad FIN

AF:

0.000400

Gnomad MID

AF:

0.0313

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.00355

GnomAD2 exomes

AF:

0.00353

AC:

854

AN:

241628

AF XY:

0.00386

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.000570

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00517

GnomAD4 exome

AF:

0.00324

AC:

4328

AN:

1335840

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

2193

AN XY:

663666

show subpopulations

African (AFR)

AF:

0.000510

AC:

AN:

29384

American (AMR)

AF:

0.00328

AC:

128

AN:

39026

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

470

AN:

22360

East Asian (EAS)

AF:

0.00

AC:

AN:

27936

South Asian (SAS)

AF:

0.00170

AC:

143

AN:

83984

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

42358

Middle Eastern (MID)

AF:

0.00808

AC:

AN:

5200

European-Non Finnish (NFE)

AF:

0.00314

AC:

3245

AN:

1033186

Other (OTH)

AF:

0.00445

AC:

233

AN:

52406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

204

408

612

816

1020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.00241

AC:

340

AN:

141066

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

145

AN XY:

67978

show subpopulations

African (AFR)

AF:

0.000335

AC:

AN:

38850

American (AMR)

AF:

0.00329

AC:

AN:

13974

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

AN:

3394

East Asian (EAS)

AF:

0.000223

AC:

AN:

4486

South Asian (SAS)

AF:

0.000703

AC:

AN:

4270

European-Finnish (FIN)

AF:

0.000400

AC:

AN:

7502

Middle Eastern (MID)

AF:

0.0301

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00301

AC:

197

AN:

65444

Other (OTH)

AF:

0.00353

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00291

Hom.:

Bravo

AF:

0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Herpes simplex encephalitis, susceptibility to, 1

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TLR3-related disorder

Benign:1

May 10, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.0

(source)

DANN

Benign

0.42

PhyloP100

-0.36

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00043

dbscSNV1_RF

Benign

0.016

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

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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