rs3804099

chr4-153703504-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001318789.2(TLR2):c.597T>C(p.Asn199=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,613,578 control chromosomes in the GnomAD database, including 155,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.47 (17482 hom., cov: 32)
  • Exomes 𝑓: 0.43 (138179 hom.)
• Consequence: TLR2 NM_001318789.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.718

Genes affected

TLR2 (HGNC:11848): (toll like receptor 2) 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. This protein is a cell-surface protein that can form heterodimers with other TLR family members to recognize conserved molecules derived from microorganisms known as pathogen-associated molecular patterns (PAMPs). Activation of TLRs by PAMPs leads to an up-regulation of signaling pathways to modulate the host's inflammatory response. This gene is also thought to promote apoptosis in response to bacterial lipoproteins. This gene has been implicated in the pathogenesis of several autoimmune diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-153703504-T-C is Benign according to our data. Variant chr4-153703504-T-C is described in ClinVar as [Benign]. Clinvar id is 3060911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.718 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR2	NM_001318789.2	c.597T>C	p.Asn199=	synonymous_variant	3/3	ENST00000642700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR2	ENST00000642700.2	c.597T>C	p.Asn199=	synonymous_variant	3/3		NM_001318789.2	P1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71322 AN: 151978 Hom.: 17450 Cov.: 32

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.479

GnomAD3 exomes AF: 0.405 AC: 101488 AN: 250696 Hom.: 21598 AF XY: 0.404 AC XY: 54735 AN XY: 135482

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.289

Gnomad SAS exome AF: 0.332

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.423

GnomAD4 exome AF: 0.432 AC: 630646 AN: 1461482 Hom.: 138179 Cov.: 51 AF XY: 0.429 AC XY: 311733 AN XY: 727018

Gnomad4 AFR exome AF: 0.617

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.431

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.376

Gnomad4 NFE exome AF: 0.445

Gnomad4 OTH exome AF: 0.430

GnomAD4 genome AF: 0.469 AC: 71398 AN: 152096 Hom.: 17482 Cov.: 32 AF XY: 0.461 AC XY: 34275 AN XY: 74322

Gnomad4 AFR AF: 0.619

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.475

Alfa AF: 0.449 Hom.: 22637

Bravo AF: 0.476

Asia WGS AF: 0.305 AC: 1065 AN: 3478

EpiCase AF: 0.444

EpiControl AF: 0.439

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TLR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.45
Dann	Benign	0.25

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: rs3804099; hg19: chr4-154624656; COSMIC: COSV52606497; COSMIC: COSV52606497;