Genetic Variant TLR3:c.633+190G>C (chr4-186079221-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003265.3(TLR3):c.633+190G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 151,932 control chromosomes in the GnomAD database, including 2,802 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 2802 hom., cov: 32)

Consequence

TLR3
NM_003265.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.380

Publications

13 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.633+190G>C		intron_variant	Intron 3 of 4	ENST00000296795.8	NP_003256.1	O15455-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TLR3	ENST00000296795.8 link	c.633+190G>C	intron_variant	Intron 3 of 4	1	NM_003265.3	ENSP00000296795.3	O15455-1
TLR3	ENST00000513189.1 link	n.633+190G>C	intron_variant	Intron 3 of 4	1		ENSP00000423386.1	D6RA51
TLR3	ENST00000698351.1 link	c.633+190G>C	intron_variant	Intron 3 of 4			ENSP00000513674.1	A0A8V8TLN9
TLR3	ENST00000698352.1 link	n.*185+190G>C	intron_variant	Intron 3 of 4			ENSP00000513675.1	A0A8V8TN43

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28192

AN:

151814

Hom.:

2798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.335

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.248

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.186

AC:

28203

AN:

151932

Hom.:

2802

Cov.:

AF XY:

0.181

AC XY:

13440

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.163

AC:

6754

AN:

41430

American (AMR)

AF:

0.145

AC:

2217

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

1162

AN:

3464

East Asian (EAS)

AF:

0.120

AC:

617

AN:

5154

South Asian (SAS)

AF:

0.245

AC:

1176

AN:

4806

European-Finnish (FIN)

AF:

0.113

AC:

1199

AN:

10582

Middle Eastern (MID)

AF:

0.257

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.212

AC:

14385

AN:

67926

Other (OTH)

AF:

0.207

AC:

436

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1165

2331

3496

4662

5827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.0909

Hom.:

144

Bravo

AF:

0.187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.41

(source)

DANN

Benign

0.50

PhyloP100

-0.38

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over