rs5743318

chr4-186083895-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003265.3(TLR3):c.2209T>A(p.Ser737Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,230 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (17 hom.)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0760

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024875104).
• BP6: Variant 4-186083895-T-A is Benign according to our data. Variant chr4-186083895-T-A is described in ClinVar as [Benign]. Clinvar id is 470481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1553/152354) while in subpopulation AFR AF= 0.0355 (1475/41568). AF 95% confidence interval is 0.034. There are 28 homozygotes in gnomad4. There are 708 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR3	NM_003265.3	c.2209T>A	p.Ser737Thr	missense_variant	4/5	ENST00000296795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR3	ENST00000296795.8	c.2209T>A	p.Ser737Thr	missense_variant	4/5	1	NM_003265.3	P1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1551 AN: 152236 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00252 AC: 633 AN: 251298 Hom.: 8 AF XY: 0.00171 AC XY: 232 AN XY: 135846

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000949 AC: 1388 AN: 1461876 Hom.: 17 Cov.: 36 AF XY: 0.000828 AC XY: 602 AN XY: 727238

Gnomad4 AFR exome AF: 0.0340

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.0102 AC: 1553 AN: 152354 Hom.: 28 Cov.: 32 AF XY: 0.00950 AC XY: 708 AN XY: 74514

Gnomad4 AFR AF: 0.0355

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00153 Hom.: 4

Bravo AF: 0.0115

ESP6500AA AF: 0.0327 AC: 144

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00297 AC: 360

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	15
Dann	Benign	0.71
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.031
Sift	Benign	0.17	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0020	B;.
Vest4		0.12
MVP		0.49
MPC		0.12
ClinPred		0.0012	T
GERP RS		1.4
Varity_R		0.053
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs5743318; hg19: chr4-187005049;