Menu
GeneBe

rs3775291

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_003265.3(TLR3):c.1234C>G(p.Leu412Val) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,613,818 control chromosomes in the GnomAD database, including 1 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. L412F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

TLR3
NM_003265.3 missense

Scores

5
10
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TLR3NM_003265.3 linkuse as main transcriptc.1234C>G p.Leu412Val missense_variant 4/5 ENST00000296795.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TLR3ENST00000296795.8 linkuse as main transcriptc.1234C>G p.Leu412Val missense_variant 4/51 NM_003265.3 P1O15455-1

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152026
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000948
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000124
AC:
31
AN:
250924
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.000238
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000324
AC:
473
AN:
1461792
Hom.:
1
Cov.:
55
AF XY:
0.000319
AC XY:
232
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.000406
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152026
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74240
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000948
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.000124
AC:
15
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

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
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 24, 2023This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 412 of the TLR3 protein (p.Leu412Val). This variant is present in population databases (rs3775291, 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: 656784). 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. 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
0.25
BayesDel_addAF
Benign
-0.0051
T
BayesDel_noAF
Uncertain
0.050
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Benign
0.30
T;.;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Uncertain
0.73
D;D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
3.4
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-2.6
D;N;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.33
MutPred
0.51
Loss of sheet (P = 0.0457);.;.;
MVP
0.93
MPC
0.49
ClinPred
0.45
T
GERP RS
5.0
Varity_R
0.77
gMVP
0.42

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.

Other links and lift over

dbSNP: rs3775291; hg19: chr4-187004074; API