rs5743708

Positions:

• chr4-153705165-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001318789.2(TLR2):​c.2258G>A​(p.Arg753Gln) variant causes a missense change. The variant allele was found at a frequency of 0.025 in 1,614,052 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (40 hom., cov: 32)
  • Exomes 𝑓: 0.026 (592 hom.)
• Consequence: TLR2 NM_001318789.2 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 6.79

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009150982).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0177 (2699/152180) while in subpopulation NFE AF= 0.0294 (1998/67988). AF 95% confidence interval is 0.0283. There are 40 homozygotes in gnomad4. There are 1268 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 40 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR2	NM_001318789.2	c.2258G>A	p.Arg753Gln	missense_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.2258G>A	p.Arg753Gln	missense_variant	3/3		NM_001318789.2	ENSP00000494425	P1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2701 AN: 152062 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0174 AC: 4375 AN: 251060 Hom.: 80 AF XY: 0.0173 AC XY: 2355 AN XY: 135790

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.00746

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0257 AC: 37626 AN: 1461872 Hom.: 592 Cov.: 34 AF XY: 0.0250 AC XY: 18208 AN XY: 727234

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.00606

Gnomad4 ASJ exome AF: 0.00765

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.0322

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0177 AC: 2699 AN: 152180 Hom.: 40 Cov.: 32 AF XY: 0.0170 AC XY: 1268 AN XY: 74394

Gnomad4 AFR AF: 0.00417

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0250 Hom.: 39

Bravo AF: 0.0151

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0309 AC: 266

ExAC AF: 0.0172 AC: 2093

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0219

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Mycobacterium tuberculosis, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 02, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T;T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;.;D;T
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	M;M;M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	.;.;.;D;.
REVEL	Benign	0.24
Sift	Pathogenic	0.0	.;.;.;D;.
Sift4G	Uncertain	0.016	.;.;.;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.20
MPC		0.43
ClinPred		0.014	T
GERP RS		5.6
Varity_R		0.81
gMVP		0.58

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: rs5743708; hg19: chr4-154626317; COSMIC: COSV52605106; COSMIC: COSV52605106;