4-186083613-C-T

Variant names:

• chr4-186083613-C-T
• rs73025939
• NM_003265.3:c.1927C>T
• TLR3 p.Arg643Cys

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003265.3(TLR3):​c.1927C>T​(p.Arg643Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000972 in 1,605,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R643S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0500
• Publications: 7 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: AD, AR, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2367346).

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.1927C>T	p.Arg643Cys	missense	Exon 4 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.1927C>T	p.Arg643Cys	missense	Exon 4 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000512264.1	TSL:1	c.1096C>T	p.Arg366Cys	missense	Exon 1 of 2	ENSP00000513668.1	O15455-2
	TLR3	ENST00000949725.1		c.1927C>T	p.Arg643Cys	missense	Exon 4 of 5	ENSP00000619784.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000575 AC: 14 AN: 243514 AF XY: 0.0000455

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1453446 Hom.: 0 Cov.: 36 AF XY: 0.0000941 AC XY: 68 AN XY: 722290

African (AFR) AF: 0.0000303 AC: 1 AN: 33006

American (AMR) AF: 0.00 AC: 0 AN: 43134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000592 AC: 5 AN: 84424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1108640

Other (OTH) AF: 0.000100 AC: 6 AN: 60000

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 19

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.40	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.050
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.036	D
Varity_R		0.19
gMVP		0.59
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs73025939;

hg19: chr4-187004767;

COSMIC: COSV105110991;