rs121434431

Positions:

chr4-186083346-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000296795.8(TLR3):c.1660C>T(p.Pro554Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000511 in 1,614,052 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 2 hom. )

Consequence

TLR3
ENST00000296795.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 6.15

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR3	NM_003265.3 linkuse as main transcript	c.1660C>T	p.Pro554Ser	missense_variant	4/5	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8 linkuse as main transcript	c.1660C>T	p.Pro554Ser	missense_variant	4/5	1	NM_003265.3	ENSP00000296795	P1	O15455-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000406

AC:

102

AN:

251312

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000687

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000513

AC:

750

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000531

AC XY:

386

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.000605

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000493

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000677

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 19, 2019

The p.Pro554Ser variant in TLR3 has been reported in 2 heterozygous and 1 compound heterozygous individuals with herpes simplex encephalitis (HSE), and 1 heterozygous proband with enteroviral myocarditis (Zhang 2007, Gorbea 2010, Guo 2011). However, it has also been identified in multiple unaffected family members (Zhang 2007, Guo 2011) and in 0.07% (91/129040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported as a variant of uncertain significance in ClinVar (Variation ID 6662). Computational prediction tools and conservation analysis suggest that the p.Pro554Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, in vitro functional assays have produced conflicting results regarding the impact of this variant on protein function (Zhang 2007, Wang 2009, Gorbea 2010, Qi 2010, Guo 2011). Finally, although TLR3 variants have been reported in association with HSE, this gene-disease relationship has not been definitively established. In summary, the clinical significance of the p.Pro554Ser variant is uncertain. -

Herpes simplex encephalitis, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 554 of the TLR3 protein (p.Pro554Ser). This variant is present in population databases (rs121434431, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with herpes simplex encephalitis, severe influenza pneumonia, and/or recurrent herpes simplex virus 1‚Äìtriggered erythema multiforme (PMID: 17872438, 21911422, 33174085, 34813006). ClinVar contains an entry for this variant (Variation ID: 6662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TLR3 function (PMID: 17872438, 19625408, 20472559, 20855885). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TLR3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

The TLR3 c.1660C>T variant is predicted to result in the amino acid substitution p.Pro554Ser. This variant has been reported in the heterozygous and compound heterozygous states in at least three individuals with acute, infection-induced herpes-specific encephalitis (HSE) (Zhang et al. 2007. PubMed ID: 17872438; Guo et al. 2011. PubMed ID: 21911422) and at least four individuals with severe influenza-induced pneumonia (Lim et al. 2019. PubMed ID: 31217193; Bucciol et al. 2022. PubMed ID: 34813006). It has also been reported in an individual with recurrent HSV1–triggered erythema multiforme and no history of HSE (Bucciol et al. 2021. PubMed ID: 33174085), one individual with Coxsackievirus B3 (CVB3)-associated myocarditis (Gorbea et al. 2010. PubMed ID: 20472559), and one individual from a cohort of patients who experienced "life-threatening" COVID-19 (Zhang et al. 2020. PubMed ID: 32972995). In vitro studies are inconclusive or conflicting regarding a possible impact on protein function. One study investigating the antiviral immune response to hepatitis C virus found that the p.Pro554Ser variant generated an immune response comparable to wild type in transformed hepatocytes (Wang et al. 2009. PubMed ID: 19625408). Another study found that p.Pro554Ser was able to generate a normal immune response but had reduced expression at the cell surface indicative of a possible intracellular trafficking defect (Qi et al. 2010. PubMed ID: 20855885). On the other hand, several additional studies have demonstrated a complete loss of function in patient fibroblasts or transformed, TLR3-deficient fibrosarcoma cell lines (Zhang et al. 2007. PubMed ID: 17872438; Guo et al. 2011. PubMed ID: 21911422; Lim et al. 2019. PubMed ID: 31217193; Zhang et al. 2020. PubMed ID: 32972995). This variant is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Incomplete penetrance has been reported in several studies (Zhang et al. 2007. PubMed ID: 17872438; Guo et al. 2011. PubMed ID: 21911422; reviewed in Mielcarska et al. 2018. PubMed ID: 29305044). Taken together, the clinical significance of the p.Pro554Ser variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Immunodeficiency 83, susceptibility to viral infections

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 14, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.69

MVP

0.89

MPC

0.58

ClinPred

0.13

GERP RS

4.8

Varity_R

0.80

gMVP

0.62

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