rs5743318

Positions:

chr4-186083895-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003265.3(TLR3):c.2209T>A(p.Ser737Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,230 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 28 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 17 hom. )

Consequence

TLR3
NM_003265.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0760

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024875104).

BP6

Variant 4-186083895-T-A is Benign according to our data. Variant chr4-186083895-T-A is described in ClinVar as [Benign]. Clinvar id is 470481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1553/152354) while in subpopulation AFR AF= 0.0355 (1475/41568). AF 95% confidence interval is 0.034. There are 28 homozygotes in gnomad4. There are 708 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR3	NM_003265.3 linkuse as main transcript	c.2209T>A	p.Ser737Thr	missense_variant	4/5	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8 linkuse as main transcript	c.2209T>A	p.Ser737Thr	missense_variant	4/5	1	NM_003265.3	ENSP00000296795	P1	O15455-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1551

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0355

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00907

GnomAD3 exomes

AF:

0.00252

AC:

633

AN:

251298

Hom.:

AF XY:

0.00171

AC XY:

232

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0345

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000949

AC:

1388

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000828

AC XY:

602

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0340

Gnomad4 AMR exome

AF:

0.00181

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.0102

AC:

1553

AN:

152354

Hom.:

Cov.:

AF XY:

0.00950

AC XY:

708

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0355

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.0115

ESP6500AA

AF:

0.0327

AC:

144

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00297

AC:

360

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

0.43

N;N

REVEL

Benign

0.031

Sift

Benign

0.17

T;T

Sift4G

Benign

0.61

T;T

Polyphen

0.0020

B;.

Vest4

0.12

MVP

0.49

MPC

0.12

ClinPred

0.0012

GERP RS

1.4

Varity_R

0.053

gMVP

0.50

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over