rs73025939

chr4-186083613-C-Achr4-186083613-C-T

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.1927C>A(p.Arg643Ser) 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 1,605,718 control chromosomes in the GnomAD database, including 49 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R643C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: TLR3 NM_003265.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0500

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=0.00221923).
• BP6: Variant 4-186083613-C-A is Benign according to our data. Variant chr4-186083613-C-A is described in ClinVar as [Benign]. Clinvar id is 470480.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-186083613-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00956 (1456/152276) while in subpopulation AFR AF= 0.0335 (1393/41554). AF 95% confidence interval is 0.0321. There are 30 homozygotes in gnomad4. There are 678 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR3	NM_003265.3	c.1927C>A	p.Arg643Ser	missense_variant	4/5	ENST00000296795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR3	ENST00000296795.8	c.1927C>A	p.Arg643Ser	missense_variant	4/5	1	NM_003265.3	P1

Frequencies

GnomAD3 genomes AF: 0.00955 AC: 1453 AN: 152158 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00239 AC: 581 AN: 243514 Hom.: 7 AF XY: 0.00178 AC XY: 234 AN XY: 131802

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000699

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.00101 AC: 1465 AN: 1453442 Hom.: 19 Cov.: 36 AF XY: 0.000889 AC XY: 642 AN XY: 722288

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000948

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000406

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00956 AC: 1456 AN: 152276 Hom.: 30 Cov.: 33 AF XY: 0.00911 AC XY: 678 AN XY: 74450

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00138 Hom.: 7

Bravo AF: 0.0102

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00296 AC: 359

Asia WGS AF: 0.00202 AC: 9 AN: 3478

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 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.0080
Dann	Benign	0.48
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.78	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.089
Sift	Benign	0.49	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.011	B;.
Vest4		0.072
MVP		0.26
MPC		0.15
ClinPred		0.0036	T
GERP RS		-12
Varity_R		0.22
gMVP		0.44

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: rs73025939; hg19: chr4-187004767;