Genetic Variant TLR3:p.Leu412Val (chr4-186082920-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10

Publications

454 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: Uncertain_significance. The variant received 0 ACMG points.

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.1234C>G	p.Leu412Val	missense	Exon 4 of 5	NP_003256.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TLR3	ENST00000296795.8	TSL:1 MANE Select	c.1234C>G	p.Leu412Val	missense	Exon 4 of 5	ENSP00000296795.3
TLR3	ENST00000512264.1	TSL:1	c.403C>G	p.Leu135Val	missense	Exon 1 of 2	ENSP00000513668.1
TLR3	ENST00000513189.1	TSL:1	n.1042C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000423386.1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152026

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000124

AC:

AN:

250924

AF XY:

0.000103

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 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.:

Cov.:

AF XY:

0.000319

AC XY:

232

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000406

AC:

452

AN:

1111954

Other (OTH)

AF:

0.000149

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.0000855

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000948

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00

Hom.:

27714

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Herpes simplex encephalitis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0051

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

3.4

PhyloP100

4.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.33

MutPred

0.51

Loss of sheet (P = 0.0457)

MVP

0.93

MPC

0.49

ClinPred

0.45

GERP RS

5.0

Varity_R

0.77

gMVP

0.42

Mutation Taster

=57/43

polymorphism

(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

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