rs3775296

Variant names:

• chr4-186076613-C-A
• rs3775296
• NM_003265.3:c.-7C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-186076613-C-A
• chr4-186076613-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003265.3(TLR3):​c.-7C>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,612,512 control chromosomes in the GnomAD database, including 28,787 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2521 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26266 hom.)
• Consequence: TLR3 NM_003265.3 splice_region
• Scores: Splicing: ADA: 0.0001301
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.225
• Publications: 93 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-186076613-C-A is Benign according to our data. Variant chr4-186076613-C-A is described in ClinVar as Benign. ClinVar VariationId is 1166908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 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.-7C>A		splice_region	Exon 2 of 5	NP_003256.1	O15455-1
	TLR3	NM_003265.3	MANE Select	c.-7C>A		5_prime_UTR	Exon 2 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.-7C>A		splice_region	Exon 2 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000296795.8	TSL:1 MANE Select	c.-7C>A		5_prime_UTR	Exon 2 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000513189.1	TSL:1	n.-7C>A		splice_region non_coding_transcript_exon	Exon 2 of 5	ENSP00000423386.1	D6RA51

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27278 AN: 151984 Hom.: 2520 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.183 AC: 45900 AN: 251148 AF XY: 0.182

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.188 AC: 274876 AN: 1460410 Hom.: 26266 Cov.: 33 AF XY: 0.188 AC XY: 136340 AN XY: 726570

African (AFR) AF: 0.158 AC: 5274 AN: 33452

American (AMR) AF: 0.172 AC: 7673 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4143 AN: 26132

East Asian (EAS) AF: 0.259 AC: 10288 AN: 39694

South Asian (SAS) AF: 0.164 AC: 14096 AN: 86150

European-Finnish (FIN) AF: 0.184 AC: 9832 AN: 53386

Middle Eastern (MID) AF: 0.159 AC: 917 AN: 5768

European-Non Finnish (NFE) AF: 0.190 AC: 211395 AN: 1110764

Other (OTH) AF: 0.187 AC: 11258 AN: 60352

GnomAD4 genome AF: 0.179 AC: 27295 AN: 152102 Hom.: 2521 Cov.: 32 AF XY: 0.180 AC XY: 13373 AN XY: 74334

African (AFR) AF: 0.153 AC: 6356 AN: 41498

American (AMR) AF: 0.178 AC: 2718 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3468

East Asian (EAS) AF: 0.249 AC: 1284 AN: 5160

South Asian (SAS) AF: 0.168 AC: 811 AN: 4818

European-Finnish (FIN) AF: 0.181 AC: 1916 AN: 10572

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12990 AN: 67992

Other (OTH) AF: 0.173 AC: 366 AN: 2110

Alfa AF: 0.188 Hom.: 13171

Bravo AF: 0.178

Asia WGS AF: 0.205 AC: 710 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.186

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.7
DANN	Benign	0.56
PhyloP100		-0.23
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0080
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: rs3775296; hg19: chr4-186997767; COSMIC: COSV57167895; COSMIC: COSV57167895;