4-186082920-C-T

Variant names:

• chr4-186082920-C-T
• rs3775291
• NM_003265.3:c.1234C>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.1234C>T​(p.Leu412Phe) variant causes a missense change. The variant allele was found at a frequency of 0.284 in 1,613,766 control chromosomes in the GnomAD database, including 67,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L412V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (5155 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62517 hom.)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.10
• Publications: 454 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: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021493137).
• BP6: Variant 4-186082920-C-T is Benign according to our data. Variant chr4-186082920-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR3	NM_003265.3	MANE Select	c.1234C>T	p.Leu412Phe	missense	Exon 4 of 5	NP_003256.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR3	ENST00000296795.8	TSL:1 MANE Select	c.1234C>T	p.Leu412Phe	missense	Exon 4 of 5	ENSP00000296795.3
	TLR3	ENST00000512264.1	TSL:1	c.403C>T	p.Leu135Phe	missense	Exon 1 of 2	ENSP00000513668.1
	TLR3	ENST00000513189.1	TSL:1	n.1042C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000423386.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35941 AN: 151972 Hom.: 5148 Cov.: 32

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.279 AC: 70051 AN: 250924 AF XY: 0.280

Gnomad AFR exome AF: 0.0647

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.289 AC: 421977 AN: 1461676 Hom.: 62517 Cov.: 55 AF XY: 0.287 AC XY: 208939 AN XY: 727126

African (AFR) AF: 0.0604 AC: 2023 AN: 33480

American (AMR) AF: 0.298 AC: 13331 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6704 AN: 26132

East Asian (EAS) AF: 0.299 AC: 11879 AN: 39698

South Asian (SAS) AF: 0.240 AC: 20729 AN: 86232

European-Finnish (FIN) AF: 0.323 AC: 17269 AN: 53394

Middle Eastern (MID) AF: 0.247 AC: 1423 AN: 5766

European-Non Finnish (NFE) AF: 0.298 AC: 331842 AN: 1111880

Other (OTH) AF: 0.278 AC: 16777 AN: 60378

GnomAD4 genome AF: 0.236 AC: 35960 AN: 152090 Hom.: 5155 Cov.: 32 AF XY: 0.238 AC XY: 17727 AN XY: 74334

African (AFR) AF: 0.0691 AC: 2868 AN: 41530

American (AMR) AF: 0.314 AC: 4793 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3472

East Asian (EAS) AF: 0.322 AC: 1664 AN: 5164

South Asian (SAS) AF: 0.246 AC: 1184 AN: 4814

European-Finnish (FIN) AF: 0.323 AC: 3411 AN: 10546

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20272 AN: 67982

Other (OTH) AF: 0.283 AC: 596 AN: 2108

Alfa AF: 0.276 Hom.: 27714

Bravo AF: 0.227

TwinsUK AF: 0.301 AC: 1117

ALSPAC AF: 0.287 AC: 1105

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.290 AC: 2496

ExAC AF: 0.271 AC: 32913

Asia WGS AF: 0.297 AC: 1036 AN: 3478

EpiCase AF: 0.287

EpiControl AF: 0.291

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 83, susceptibility to viral infections (2)
-	-	2	not provided (2)
-	-	1	Herpes simplex encephalitis, susceptibility to, 1 (1)
-	-	1	not specified (1)
-	-	1	Susceptibility to HIV infection;C2751803:Immunodeficiency 83, susceptibility to viral infections (1)
-	-	1	TLR3-related disorder (1)
-	-	-	Susceptibility to HIV infection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.4	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.20
MPC		0.34
ClinPred		0.082	T
GERP RS		5.0
Varity_R		0.81
gMVP		0.57
Mutation Taster		=59/41	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: rs3775291; hg19: chr4-187004074; COSMIC: COSV57167912; COSMIC: COSV57167912;