chr4-186076613-C-A

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.-7C>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,612,512 control chromosomes in the GnomAD database, including 28,787 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2521 hom., cov: 32)

Exomes 𝑓: 0.19 ( 26266 hom. )

Consequence

TLR3
NM_003265.3 splice_region

Scores

Splicing: ADA: 0.0001301

Clinical Significance

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

Conservation

PhyloP100: -0.225

Publications

93 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 (BayesDel_noAF=-0.76).

BP6

Variant 4-186076613-C-A is Benign according to our data. Variant chr4-186076613-C-A is described in ClinVar as Benign. ClinVar VariationId is 1166908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.-7C>A		splice_region_variant	Exon 2 of 5	ENST00000296795.8	NP_003256.1	O15455-1
TLR3	NM_003265.3 link	c.-7C>A		5_prime_UTR_variant	Exon 2 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.-7C>A		splice_region_variant	Exon 2 of 5	1	NM_003265.3	ENSP00000296795.3		O15455-1
TLR3	ENST00000296795.8 link	c.-7C>A		5_prime_UTR_variant	Exon 2 of 5	1	NM_003265.3	ENSP00000296795.3		O15455-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27278

AN:

151984

Hom.:

2520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.249

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.191

Gnomad OTH

AF:

0.172

GnomAD2 exomes

AF:

0.183

AC:

45900

AN:

251148

AF XY:

0.182

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.170

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.188

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.183

GnomAD4 exome

AF:

0.188

AC:

274876

AN:

1460410

Hom.:

26266

Cov.:

AF XY:

0.188

AC XY:

136340

AN XY:

726570

show subpopulations

African (AFR)

AF:

0.158

AC:

5274

AN:

33452

American (AMR)

AF:

0.172

AC:

7673

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4143

AN:

26132

East Asian (EAS)

AF:

0.259

AC:

10288

AN:

39694

South Asian (SAS)

AF:

0.164

AC:

14096

AN:

86150

European-Finnish (FIN)

AF:

0.184

AC:

9832

AN:

53386

Middle Eastern (MID)

AF:

0.159

AC:

917

AN:

5768

European-Non Finnish (NFE)

AF:

0.190

AC:

211395

AN:

1110764

Other (OTH)

AF:

0.187

AC:

11258

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

11204

22408

33612

44816

56020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7460

14920

22380

29840

37300

<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:

0.179

AC:

27295

AN:

152102

Hom.:

2521

Cov.:

AF XY:

0.180

AC XY:

13373

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.153

AC:

6356

AN:

41498

American (AMR)

AF:

0.178

AC:

2718

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

540

AN:

3468

East Asian (EAS)

AF:

0.249

AC:

1284

AN:

5160

South Asian (SAS)

AF:

0.168

AC:

811

AN:

4818

European-Finnish (FIN)

AF:

0.181

AC:

1916

AN:

10572

Middle Eastern (MID)

AF:

0.140

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.191

AC:

12990

AN:

67992

Other (OTH)

AF:

0.173

AC:

366

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1157

2314

3470

4627

5784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.188

Hom.:

13171

Bravo

AF:

0.178

Asia WGS

AF:

0.205

AC:

710

AN:

3478

EpiCase

AF:

0.188

EpiControl

AF:

0.186

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -

Herpes simplex encephalitis, susceptibility to, 1

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.7

(source)

DANN

Benign

0.56

PhyloP100

-0.23

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.0080

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