4-186079102-C-T

Variant names:

• chr4-186079102-C-T
• rs5743312
• NM_003265.3:c.633+71C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003265.3(TLR3):​c.633+71C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,316,630 control chromosomes in the GnomAD database, including 15,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1594 hom., cov: 32)
  • Exomes 𝑓: 0.15 (13948 hom.)
• Consequence: TLR3 NM_003265.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.872
• Publications: 47 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3	c.633+71C>T		intron_variant	Intron 3 of 4	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8	c.633+71C>T		intron_variant	Intron 3 of 4	1	NM_003265.3	ENSP00000296795.3
TLR3	ENST00000513189.1	n.633+71C>T		intron_variant	Intron 3 of 4	1		ENSP00000423386.1
TLR3	ENST00000698351.1	c.633+71C>T		intron_variant	Intron 3 of 4			ENSP00000513674.1
TLR3	ENST00000698352.1	n.*185+71C>T		intron_variant	Intron 3 of 4			ENSP00000513675.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21382 AN: 152092 Hom.: 1593 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.151 AC: 176226 AN: 1164420 Hom.: 13948 AF XY: 0.151 AC XY: 88949 AN XY: 587408

African (AFR) AF: 0.104 AC: 2788 AN: 26912

American (AMR) AF: 0.141 AC: 5151 AN: 36656

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3135 AN: 23580

East Asian (EAS) AF: 0.251 AC: 8926 AN: 35628

South Asian (SAS) AF: 0.144 AC: 10718 AN: 74454

European-Finnish (FIN) AF: 0.139 AC: 7000 AN: 50222

Middle Eastern (MID) AF: 0.137 AC: 496 AN: 3608

European-Non Finnish (NFE) AF: 0.151 AC: 130260 AN: 863236

Other (OTH) AF: 0.155 AC: 7752 AN: 50124

GnomAD4 genome AF: 0.141 AC: 21399 AN: 152210 Hom.: 1594 Cov.: 32 AF XY: 0.141 AC XY: 10501 AN XY: 74418

African (AFR) AF: 0.104 AC: 4326 AN: 41538

American (AMR) AF: 0.141 AC: 2160 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1259 AN: 5180

South Asian (SAS) AF: 0.154 AC: 743 AN: 4822

European-Finnish (FIN) AF: 0.130 AC: 1373 AN: 10590

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10543 AN: 68000

Other (OTH) AF: 0.149 AC: 314 AN: 2110

Alfa AF: 0.147 Hom.: 924

Bravo AF: 0.141

Asia WGS AF: 0.191 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.073
DANN	Benign	0.22
PhyloP100		-0.87
Mutation Taster		=100/0	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: rs5743312; hg19: chr4-187000256;