rs35111588

Variant names:

• chr4-186083390-C-T
• rs35111588
• NM_003265.3:c.1704C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003265.3(TLR3):​c.1704C>T​(p.Asn568Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,614,106 control chromosomes in the GnomAD database, including 1,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (603 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (504 hom.)
• Consequence: TLR3 NM_003265.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.389
• Publications: 4 publications found

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: AR, AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-186083390-C-T is Benign according to our data. Variant chr4-186083390-C-T is described in ClinVar as Benign. ClinVar VariationId is 470478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.389 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

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.1704C>T	p.Asn568Asn	synonymous	Exon 4 of 5	NP_003256.1	O15455-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR3	ENST00000296795.8	TSL:1 MANE Select	c.1704C>T	p.Asn568Asn	synonymous	Exon 4 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000512264.1	TSL:1	c.873C>T	p.Asn291Asn	synonymous	Exon 1 of 2	ENSP00000513668.1	O15455-2
	TLR3	ENST00000949725.1		c.1704C>T	p.Asn568Asn	synonymous	Exon 4 of 5	ENSP00000619784.1

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7450 AN: 152100 Hom.: 602 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0128 AC: 3224 AN: 251316 AF XY: 0.00931

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00507 AC: 7418 AN: 1461888 Hom.: 504 Cov.: 36 AF XY: 0.00441 AC XY: 3207 AN XY: 727244

African (AFR) AF: 0.165 AC: 5536 AN: 33478

American (AMR) AF: 0.0109 AC: 488 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5768

European-Non Finnish (NFE) AF: 0.000500 AC: 556 AN: 1112012

Other (OTH) AF: 0.0117 AC: 708 AN: 60396

GnomAD4 genome AF: 0.0491 AC: 7475 AN: 152218 Hom.: 603 Cov.: 32 AF XY: 0.0471 AC XY: 3504 AN XY: 74410

African (AFR) AF: 0.170 AC: 7067 AN: 41488

American (AMR) AF: 0.0176 AC: 269 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68030

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0269 Hom.: 192

Bravo AF: 0.0552

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Herpes simplex encephalitis, susceptibility to, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.2
DANN	Benign	0.63
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35111588; hg19: chr4-187004544;