Genetic Variant NM_003265.3:c.2553C>T (chr4-186084711-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003265.3(TLR3):c.2553C>T(p.Phe851Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,613,804 control chromosomes in the GnomAD database, including 1,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 540 hom., cov: 33)

Exomes 𝑓: 0.016 ( 674 hom. )

Consequence

TLR3
NM_003265.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.854

Publications

7 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 4-186084711-C-T is Benign according to our data. Variant chr4-186084711-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 470483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.854 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3 link	c.2553C>T	p.Phe851Phe	synonymous_variant	Exon 5 of 5	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8 link	c.2553C>T	p.Phe851Phe	synonymous_variant	Exon 5 of 5	1	NM_003265.3	ENSP00000296795.3

Frequencies

GnomAD3 genomes

AF:

0.0542

AC:

8240

AN:

151996

Hom.:

537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.00718

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0446

GnomAD2 exomes

AF:

0.0227

AC:

5704

AN:

251314

AF XY:

0.0199

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.0219

Gnomad ASJ exome

AF:

0.0356

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00661

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0274

GnomAD4 exome

AF:

0.0162

AC:

23683

AN:

1461690

Hom.:

674

Cov.:

AF XY:

0.0156

AC XY:

11308

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.169

AC:

5644

AN:

33450

American (AMR)

AF:

0.0239

AC:

1069

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

897

AN:

26128

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39674

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86252

European-Finnish (FIN)

AF:

0.00732

AC:

391

AN:

53414

Middle Eastern (MID)

AF:

0.0669

AC:

386

AN:

5766

European-Non Finnish (NFE)

AF:

0.0122

AC:

13609

AN:

1111898

Other (OTH)

AF:

0.0246

AC:

1486

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1126

2251

3377

4502

5628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.0543

AC:

8262

AN:

152114

Hom.:

540

Cov.:

AF XY:

0.0527

AC XY:

3919

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.156

AC:

6449

AN:

41472

American (AMR)

AF:

0.0324

AC:

495

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00396

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00718

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0140

AC:

952

AN:

68000

Other (OTH)

AF:

0.0436

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

371

743

1114

1486

1857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0350

Hom.:

122

Bravo

AF:

0.0630

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0192

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.8

(source)

DANN

Benign

0.60

PhyloP100

0.85

Mutation Taster

=93/7

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over