rs3775290

Variant names:

• chr4-186083063-C-T
• rs3775290
• NM_003265.3:c.1377C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-186083063-C-T
• chr4-186083063-C-A
• chr4-186083063-C-G

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.1377C>T​(p.Phe459Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,800 control chromosomes in the GnomAD database, including 74,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5962 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68766 hom.)
• Consequence: TLR3 NM_003265.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.944
• Publications: 133 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=-0.73).
• BP6: Variant 4-186083063-C-T is Benign according to our data. Variant chr4-186083063-C-T is described in ClinVar as Benign. ClinVar VariationId is 403543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.944 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 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.1377C>T	p.Phe459Phe	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.1377C>T	p.Phe459Phe	synonymous	Exon 4 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000512264.1	TSL:1	c.546C>T	p.Phe182Phe	synonymous	Exon 1 of 2	ENSP00000513668.1	O15455-2
	TLR3	ENST00000949725.1		c.1377C>T	p.Phe459Phe	synonymous	Exon 4 of 5	ENSP00000619784.1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41804 AN: 151866 Hom.: 5963 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.302 AC: 75834 AN: 251196 AF XY: 0.302

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.323

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.305 AC: 445532 AN: 1461816 Hom.: 68766 Cov.: 70 AF XY: 0.305 AC XY: 221921 AN XY: 727210

African (AFR) AF: 0.196 AC: 6578 AN: 33478

American (AMR) AF: 0.342 AC: 15275 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6202 AN: 26136

East Asian (EAS) AF: 0.356 AC: 14137 AN: 39700

South Asian (SAS) AF: 0.321 AC: 27671 AN: 86246

European-Finnish (FIN) AF: 0.292 AC: 15595 AN: 53408

Middle Eastern (MID) AF: 0.285 AC: 1645 AN: 5768

European-Non Finnish (NFE) AF: 0.306 AC: 340150 AN: 1111964

Other (OTH) AF: 0.303 AC: 18279 AN: 60392

GnomAD4 genome AF: 0.275 AC: 41827 AN: 151984 Hom.: 5962 Cov.: 32 AF XY: 0.278 AC XY: 20641 AN XY: 74272

African (AFR) AF: 0.199 AC: 8236 AN: 41472

American (AMR) AF: 0.304 AC: 4639 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3468

East Asian (EAS) AF: 0.335 AC: 1728 AN: 5156

South Asian (SAS) AF: 0.323 AC: 1551 AN: 4804

European-Finnish (FIN) AF: 0.288 AC: 3034 AN: 10552

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20822 AN: 67938

Other (OTH) AF: 0.271 AC: 571 AN: 2110

Alfa AF: 0.153 Hom.: 10605

Bravo AF: 0.274

Asia WGS AF: 0.311 AC: 1079 AN: 3478

EpiCase AF: 0.306

EpiControl AF: 0.301

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Herpes simplex encephalitis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.9
DANN	Benign	0.59
PhyloP100		0.94
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: rs3775290; hg19: chr4-187004217; COSMIC: COSV57167904; COSMIC: COSV57167904;