rs78726532

Variant names:

• chr4-186079310-A-G
• rs78726532
• NM_003265.3:c.633+279A>G

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+279A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 152,300 control chromosomes in the GnomAD database, including 241 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 0.039 (241 hom., cov: 32)
• Consequence: TLR3 NM_003265.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3	c.633+279A>G		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+279A>G		intron_variant	Intron 3 of 4	1	NM_003265.3	ENSP00000296795.3
TLR3	ENST00000513189.1	n.633+279A>G		intron_variant	Intron 3 of 4	1		ENSP00000423386.1
TLR3	ENST00000698351.1	c.633+279A>G		intron_variant	Intron 3 of 4			ENSP00000513674.1
TLR3	ENST00000698352.1	n.*185+279A>G		intron_variant	Intron 3 of 4			ENSP00000513675.1

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5894 AN: 152182 Hom.: 239 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0339

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0388 AC: 5903 AN: 152300 Hom.: 241 Cov.: 32 AF XY: 0.0371 AC XY: 2766 AN XY: 74474

African (AFR) AF: 0.101 AC: 4190 AN: 41556

American (AMR) AF: 0.0284 AC: 434 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10620

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 923 AN: 68032

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0287 Hom.: 23

Bravo AF: 0.0442

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.32
DANN	Benign	0.35
PhyloP100		-1.2
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: rs78726532; hg19: chr4-187000464;