rs35311343

chr4-186082575-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_003265.3(TLR3):c.889C>G(p.Leu297Val) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,614,170 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:2
• Conservation: PhyloP100: 3.80

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035041124).
• BP6: Variant 4-186082575-C-G is Benign according to our data. Variant chr4-186082575-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 495314.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-186082575-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR3	NM_003265.3	c.889C>G	p.Leu297Val	missense_variant	4/5	ENST00000296795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR3	ENST00000296795.8	c.889C>G	p.Leu297Val	missense_variant	4/5	1	NM_003265.3	P1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00148 AC: 373 AN: 251348 Hom.: 1 AF XY: 0.00148 AC XY: 201 AN XY: 135870

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00207 AC: 3020 AN: 1461858 Hom.: 4 Cov.: 37 AF XY: 0.00199 AC XY: 1448 AN XY: 727230

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74482

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.00169

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00218

EpiControl AF: 0.00207

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Multisystem inflammatory syndrome in children Other:1

risk factor, no assertion criteria provided

research

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Nov 14, 2021

- -

Immunodeficiency 83, susceptibility to viral infections Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.035	T;T
MetaSVM	Uncertain	0.073	D
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;T
Sift4G	Uncertain	0.012	D;D
Polyphen		0.98	D;.
Vest4		0.65
MVP		0.93
MPC		0.57
ClinPred		0.059	T
GERP RS		5.4
Varity_R		0.64
gMVP		0.54

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: rs35311343; hg19: chr4-187003729; COSMIC: COSV105111034;