4-186076795-C-T

Position:

• chr4-186076795-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003265.3(TLR3):​c.176C>T​(p.Thr59Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T59N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR3	NM_003265.3	c.176C>T	p.Thr59Ile	missense_variant	2/5	ENST00000296795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR3	ENST00000296795.8	c.176C>T	p.Thr59Ile	missense_variant	2/5	1	NM_003265.3	P1
TLR3	ENST00000513189.1	c.176C>T	p.Thr59Ile	missense_variant	2/5	1
TLR3	ENST00000698351.1	c.176C>T	p.Thr59Ile	missense_variant	2/5
TLR3	ENST00000698352.1	c.176C>T	p.Thr59Ile	missense_variant, NMD_transcript_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.94	P;.
Vest4		0.45
MutPred		0.67		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.85
MPC		0.46
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143307508; hg19: chr4-186997949;