4-186083346-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003265.3(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P554H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 2 hom. )

Consequence

TLR3
NM_003265.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 6.15

Publications

66 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: AD, Unknown, AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

TLR3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003265.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003265.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR3	NM_003265.3	MANE Select	c.1660C>T	p.Pro554Ser	missense	Exon 4 of 5	NP_003256.1	O15455-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR3	ENST00000296795.8	TSL:1 MANE Select	c.1660C>T	p.Pro554Ser	missense	Exon 4 of 5	ENSP00000296795.3	O15455-1
TLR3	ENST00000512264.1	TSL:1	c.829C>T	p.Pro277Ser	missense	Exon 1 of 2	ENSP00000513668.1	O15455-2
TLR3	ENST00000949725.1		c.1660C>T	p.Pro554Ser	missense	Exon 4 of 5	ENSP00000619784.1

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

GnomAD2 exomes

AF:

0.000406

AC:

102

AN:

251312

AF XY:

0.000457

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000580

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000605

AC:

673

AN:

1112008

Other (OTH)

AF:

0.000298

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

138

184

230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000493

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41436

American (AMR)

AF:

0.000196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68048

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000689

Hom.:

Bravo

AF:

0.000446

EpiCase

AF:

0.00104

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Herpes simplex encephalitis, susceptibility to, 1 (1)

not provided (1)

not specified (1)

Susceptibility to HIV infection;C2751803:Immunodeficiency 83, susceptibility to viral infections (1)

TLR3-related disorder (1)

Immunodeficiency 83, susceptibility to viral infections (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

PhyloP100

6.2

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Varity_R

0.80

gMVP

0.62

Mutation Taster

=23/77

disease causing

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over