4-186076613-C-A

Position:

• chr4-186076613-C-A

Variant summary

Our verdict is Benign. Variant got -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, 5 prime UTR 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, 5_prime_UTR
• Scores: Splicing: ADA: 0.0001301
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.225

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR3	NM_003265.3	c.-7C>A		splice_region_variant, 5_prime_UTR_variant	2/5	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8	c.-7C>A		splice_region_variant, 5_prime_UTR_variant	2/5	1	NM_003265.3	ENSP00000296795	P1
TLR3	ENST00000513189.1	c.-7C>A		splice_region_variant, 5_prime_UTR_variant	2/5	1		ENSP00000423386
TLR3	ENST00000698351.1	c.-7C>A		splice_region_variant, 5_prime_UTR_variant	2/5			ENSP00000513674
TLR3	ENST00000698352.1	c.-7C>A		splice_region_variant, 5_prime_UTR_variant, NMD_transcript_variant	2/5			ENSP00000513675

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

GnomAD3 exomes AF: 0.183 AC: 45900 AN: 251148 Hom.: 4265 AF XY: 0.182 AC XY: 24745 AN XY: 135758

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 SAS exome AF: 0.164

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

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.187

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

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.173

Alfa AF: 0.187 Hom.: 6606

Bravo AF: 0.178

Asia WGS AF: 0.205 AC: 710 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.186

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.7
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs3775296; hg19: chr4-186997767; COSMIC: COSV57167895; COSMIC: COSV57167895;