rs121434431

Variant names:

• chr4-186083346-C-T
• rs121434431
• NM_003265.3:c.1660C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003265.3(TLR3):​c.1660C>T​(p.Pro554Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000511 in 1,614,052 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 6.15
• Publications: 66 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: AR, AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD,Unknown gene

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.1660C>T	p.Pro554Ser	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.1660C>T	p.Pro554Ser	missense	Exon 4 of 5	ENSP00000296795.3	O15455-1
	TLR3	ENST00000512264.1	TSL:1	c.829C>T	p.Pro277Ser	missense	Exon 1 of 2	ENSP00000513668.1	O15455-2
	TLR3	ENST00000949725.1		c.1660C>T	p.Pro554Ser	missense	Exon 4 of 5	ENSP00000619784.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000406 AC: 102 AN: 251312 AF XY: 0.000457

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000513 AC: 750 AN: 1461882 Hom.: 2 Cov.: 36 AF XY: 0.000531 AC XY: 386 AN XY: 727238

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86250

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000605 AC: 673 AN: 1112008

Other (OTH) AF: 0.000298 AC: 18 AN: 60396

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74330

African (AFR) AF: 0.0000965 AC: 4 AN: 41436

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68048

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000689 Hom.: 1

Bravo AF: 0.000446

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.00104

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 1 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Susceptibility to HIV infection;C2751803:Immunodeficiency 83, susceptibility to viral infections (1)
-	1	-	TLR3-related disorder (1)
-	-	-	Immunodeficiency 83, susceptibility to viral infections (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.89
MPC		0.58
ClinPred		0.13	T
GERP RS		4.8
Varity_R		0.80
gMVP		0.62
Mutation Taster		=23/77	disease causing

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: rs121434431; hg19: chr4-187004500;