4-186082920-C-T

Position:

chr4-186082920-C-T

Variant summary

Our verdict is Benign. Variant got -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:8

Conservation

PhyloP100: 4.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 41472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186082920-C-T is described in Lovd as [Benign]. Variant chr4-186082920-C-T is described in Lovd as [Likely_benign].

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/exons	MANE	UniProt
TLR3	NM_003265.3 linkuse as main transcript	c.1234C>T	p.Leu412Phe	missense_variant	4/5	ENST00000296795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR3	ENST00000296795.8 linkuse as main transcript	c.1234C>T	p.Leu412Phe	missense_variant	4/5	1	NM_003265.3	P1	O15455-1

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

GnomAD3 exomes

AF:

0.279

AC:

70051

AN:

250924

Hom.:

10430

AF XY:

0.280

AC XY:

38032

AN XY:

135724

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 SAS exome

AF:

0.238

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

Gnomad4 AFR exome

AF:

0.0604

Gnomad4 AMR exome

AF:

0.298

Gnomad4 ASJ exome

AF:

0.257

Gnomad4 EAS exome

AF:

0.299

Gnomad4 SAS exome

AF:

0.240

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.298

Gnomad4 OTH exome

AF:

0.278

GnomAD4 genome

AF:

0.236

AC:

35960

AN:

152090

Hom.:

5155

Cov.:

AF XY:

0.238

AC XY:

17727

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0691

Gnomad4 AMR

AF:

0.314

Gnomad4 ASJ

AF:

0.249

Gnomad4 EAS

AF:

0.322

Gnomad4 SAS

AF:

0.246

Gnomad4 FIN

AF:

0.323

Gnomad4 NFE

AF:

0.298

Gnomad4 OTH

AF:

0.283

Alfa

AF:

0.283

Hom.:

14949

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 83, susceptibility to viral infections

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 25, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

TLR3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

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

protective, no assertion criteria provided

literature only

OMIM

Aug 08, 2018

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2019

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) -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 13, 2021

- -

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

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;.;.

MutationTaster

Benign

2.9e-8

P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over