4-186082310-C-A

Variant names:

• chr4-186082310-C-A
• rs113654222
• ENST00000512264.1:c.-208C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000512264.1(TLR3):​c.-208C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,476,906 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: TLR3 ENST00000512264.1 5_prime_UTR
• Scores: Splicing: ADA: 0.0004339
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.359
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-186082310-C-A is Benign according to our data. Variant chr4-186082310-C-A is described in ClinVar as Benign. ClinVar VariationId is 537923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000512264.1. 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.634-10C>A		intron	N/A	NP_003256.1	O15455-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR3	ENST00000512264.1	TSL:1	c.-208C>A		5_prime_UTR	Exon 1 of 2	ENSP00000513668.1	O15455-2
	TLR3	ENST00000296795.8	TSL:1 MANE Select	c.634-10C>A		intron	N/A	ENSP00000296795.3	O15455-1
	TLR3	ENST00000513189.1	TSL:1	n.634-10C>A		intron	N/A	ENSP00000423386.1	D6RA51

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 341 AN: 140980 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00330

Gnomad ASJ AF: 0.0183

Gnomad EAS AF: 0.000222

Gnomad SAS AF: 0.000702

Gnomad FIN AF: 0.000400

Gnomad MID AF: 0.0313

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00355

GnomAD2 exomes AF: 0.00353 AC: 854 AN: 241628 AF XY: 0.00386

Gnomad AFR exome AF: 0.000336

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.000570

Gnomad NFE exome AF: 0.00435

Gnomad OTH exome AF: 0.00517

GnomAD4 exome AF: 0.00324 AC: 4328 AN: 1335840 Hom.: 11 Cov.: 37 AF XY: 0.00330 AC XY: 2193 AN XY: 663666

African (AFR) AF: 0.000510 AC: 15 AN: 29384

American (AMR) AF: 0.00328 AC: 128 AN: 39026

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 470 AN: 22360

East Asian (EAS) AF: 0.00 AC: 0 AN: 27936

South Asian (SAS) AF: 0.00170 AC: 143 AN: 83984

European-Finnish (FIN) AF: 0.00123 AC: 52 AN: 42358

Middle Eastern (MID) AF: 0.00808 AC: 42 AN: 5200

European-Non Finnish (NFE) AF: 0.00314 AC: 3245 AN: 1033186

Other (OTH) AF: 0.00445 AC: 233 AN: 52406

GnomAD4 genome AF: 0.00241 AC: 340 AN: 141066 Hom.: 3 Cov.: 32 AF XY: 0.00213 AC XY: 145 AN XY: 67978

African (AFR) AF: 0.000335 AC: 13 AN: 38850

American (AMR) AF: 0.00329 AC: 46 AN: 13974

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 62 AN: 3394

East Asian (EAS) AF: 0.000223 AC: 1 AN: 4486

South Asian (SAS) AF: 0.000703 AC: 3 AN: 4270

European-Finnish (FIN) AF: 0.000400 AC: 3 AN: 7502

Middle Eastern (MID) AF: 0.0301 AC: 8 AN: 266

European-Non Finnish (NFE) AF: 0.00301 AC: 197 AN: 65444

Other (OTH) AF: 0.00353 AC: 7 AN: 1984

Alfa AF: 0.00291 Hom.: 1

Bravo AF: 0.00249

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Herpes simplex encephalitis, susceptibility to, 1 (1)
-	-	1	TLR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.42
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.010		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: rs113654222; hg19: chr4-187003464;