rs113654222

chr4-186082310-C-Achr4-186082310-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003265.3(TLR3):c.634-10C>A variant causes a splice polypyrimidine tract, intron 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 NM_003265.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004339
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.359

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 537923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186082310-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR3	NM_003265.3	c.634-10C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000296795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR3	ENST00000296795.8	c.634-10C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003265.3	P1

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

GnomAD3 exomes AF: 0.00353 AC: 854 AN: 241628 Hom.: 5 AF XY: 0.00386 AC XY: 508 AN XY: 131698

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 SAS exome AF: 0.00168

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

Gnomad4 AFR exome AF: 0.000510

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.00123

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00445

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

Gnomad4 AFR AF: 0.000335

Gnomad4 AMR AF: 0.00329

Gnomad4 ASJ AF: 0.0183

Gnomad4 EAS AF: 0.000223

Gnomad4 SAS AF: 0.000703

Gnomad4 FIN AF: 0.000400

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00353

Alfa AF: 0.00268 Hom.: 1

Bravo AF: 0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

TLR3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.0
Dann	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs113654222; hg19: chr4-187003464;