rs5743708

Variant names:

• chr4-153705165-G-A
• rs5743708
• NM_001318789.2:c.2258G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-153705165-G-A
• chr4-153705165-G-T

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. 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 rank	MANE	Protein	UniProt
TLR2	NM_001318789.2	c.2258G>A	p.Arg753Gln	missense_variant	Exon 3 of 3	ENST00000642700.2	NP_001305718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR2	ENST00000642700.2	c.2258G>A	p.Arg753Gln	missense_variant	Exon 3 of 3		NM_001318789.2	ENSP00000494425.1

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

GnomAD2 exomes AF: 0.0174 AC: 4375 AN: 251060 AF XY: 0.0173

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 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 AC: 127 AN: 33480

Gnomad4 AMR exome AF: 0.00606 AC: 271 AN: 44724

Gnomad4 ASJ exome AF: 0.00765 AC: 200 AN: 26136

Gnomad4 EAS exome AF: 0.000151 AC: 6 AN: 39700

Gnomad4 SAS exome AF: 0.00245 AC: 211 AN: 86256

Gnomad4 FIN exome AF: 0.0322 AC: 1719 AN: 53412

Gnomad4 NFE exome AF: 0.0305 AC: 33881 AN: 1112000

Gnomad4 Remaining exome AF: 0.0198 AC: 1195 AN: 60396

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 AC: 0.00416546 AN: 0.00416546

Gnomad4 AMR AF: 0.00824 AC: 0.00823852 AN: 0.00823852

Gnomad4 ASJ AF: 0.00749 AC: 0.00748848 AN: 0.00748848

Gnomad4 EAS AF: 0.000387 AC: 0.000386997 AN: 0.000386997

Gnomad4 SAS AF: 0.00269 AC: 0.00269263 AN: 0.00269263

Gnomad4 FIN AF: 0.0299 AC: 0.0298677 AN: 0.0298677

Gnomad4 NFE AF: 0.0294 AC: 0.0293875 AN: 0.0293875

Gnomad4 OTH AF: 0.0114 AC: 0.0113529 AN: 0.0113529

Alfa AF: 0.0248 Hom.: 68

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

Nov 02, 2012

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;.
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
Mutation Taster		=78/22	polymorphism (auto)

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;