chr4-186082341-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003265.3(TLR3):c.655G>A(p.Ala219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,602,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TLR3
NM_003265.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.509

Publications

6 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05312422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.655G>A	p.Ala219Thr	missense_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.655G>A	p.Ala219Thr	missense_variant	Exon 4 of 5	1	NM_003265.3	ENSP00000296795.3		O15455-1

Frequencies

GnomAD3 genomes

AF:

0.0000406

AC:

AN:

147792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000500

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000592

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250946

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000351

AC:

AN:

1454552

Hom.:

Cov.:

AF XY:

0.0000346

AC XY:

AN XY:

723580

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33316

American (AMR)

AF:

0.00

AC:

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25942

East Asian (EAS)

AF:

0.0000771

AC:

AN:

38930

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000325

AC:

AN:

1107360

Other (OTH)

AF:

0.0000501

AC:

AN:

59890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000338

AC:

AN:

147880

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

71806

show subpopulations

African (AFR)

AF:

0.0000250

AC:

AN:

40074

American (AMR)

AF:

0.00

AC:

AN:

14620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

4900

South Asian (SAS)

AF:

0.00

AC:

AN:

4634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0000592

AC:

AN:

67520

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1

Uncertain:1

Dec 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 219 of the TLR3 protein (p.Ala219Thr). This variant is present in population databases (rs192016427, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TLR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 567930). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.071

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.28

N;.

PhyloP100

0.51

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.059

Sift

Benign

0.11

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.27

B;.

Vest4

0.071

MVP

0.76

MPC

0.14

ClinPred

0.017

GERP RS

2.4

Varity_R

0.14

gMVP

0.28

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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