rs5743709

Positions:

• chr4-153705250-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001318789.2(TLR2):​c.2343G>A​(p.Ala781=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00655 in 1,583,638 control chromosomes in the GnomAD database, including 1,062 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (157 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (905 hom.)
• Consequence: TLR2 NM_001318789.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR2	NM_001318789.2	c.2343G>A	p.Ala781=	synonymous_variant	3/3	ENST00000642700.2	NP_001305718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR2	ENST00000642700.2	c.2343G>A	p.Ala781=	synonymous_variant	3/3		NM_001318789.2	ENSP00000494425	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2016 AN: 152098 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.0274 AC: 6288 AN: 229482 Hom.: 725 AF XY: 0.0206 AC XY: 2565 AN XY: 124328

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00440

Gnomad SAS exome AF: 0.000191

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.00583 AC: 8348 AN: 1431422 Hom.: 905 Cov.: 33 AF XY: 0.00496 AC XY: 3515 AN XY: 708868

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00446

Gnomad4 SAS exome AF: 0.000145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000100

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.0133 AC: 2030 AN: 152216 Hom.: 157 Cov.: 32 AF XY: 0.0158 AC XY: 1175 AN XY: 74432

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00380 Hom.: 11

Bravo AF: 0.0230

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.30
DANN	Benign	0.77

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: rs5743709; hg19: chr4-154626402;