4-186082643-C-G

Variant names:

• chr4-186082643-C-G
• NM_003265.3:c.957C>G
• TLR3 p.His319Gln

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003265.3(TLR3):​c.957C>G​(p.His319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H319H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.657
• Publications: 0 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, Unknown, AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18009669).

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.957C>G	p.His319Gln	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.957C>G	p.His319Gln	missense	Exon 4 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000512264.1	TSL:1	c.126C>G	p.His42Gln	missense	Exon 1 of 2	ENSP00000513668.1	O15455-2
	TLR3	ENST00000513189.1	TSL:1	n.864+93C>G		intron	N/A	ENSP00000423386.1	D6RA51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.3
DANN	Benign	0.50
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.66
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.025
Sift	Benign	0.29	T
Sift4G	Benign	0.41	T
Varity_R		0.11
gMVP		0.35
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

hg19: chr4-187003797;