rs5743699

Variant names:

• chr4-153704139-C-T
• rs5743699
• NM_001318789.2:c.1232C>T
• TLR2 p.Thr411Ile

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001318789.2(TLR2):​c.1232C>T​(p.Thr411Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,496 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (31 hom.)
• Consequence: TLR2 NM_001318789.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.325
• Publications: 19 publications found

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077039003).
• BP6: Variant 4-153704139-C-T is Benign according to our data. Variant chr4-153704139-C-T is described in ClinVar as Benign. ClinVar VariationId is 3053334.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00105 (1534/1461194) while in subpopulation AMR AF = 0.0278 (1240/44580). AF 95% confidence interval is 0.0265. There are 31 homozygotes in GnomAdExome4. There are 671 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318789.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR2	NM_001318789.2	MANE Select	c.1232C>T	p.Thr411Ile	missense	Exon 3 of 3	NP_001305718.1	O60603
	TLR2	NM_001318787.2		c.1232C>T	p.Thr411Ile	missense	Exon 4 of 4	NP_001305716.1	A0A0S2Z4S4
	TLR2	NM_001318790.2		c.1232C>T	p.Thr411Ile	missense	Exon 3 of 3	NP_001305719.1	A0A0S2Z4S4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR2	ENST00000642700.2	MANE Select	c.1232C>T	p.Thr411Ile	missense	Exon 3 of 3	ENSP00000494425.1	O60603
	TLR2	ENST00000260010.7	TSL:6	c.1232C>T	p.Thr411Ile	missense	Exon 3 of 3	ENSP00000260010.6	O60603
	TLR2	ENST00000642580.1		c.1232C>T	p.Thr411Ile	missense	Exon 3 of 3	ENSP00000495339.1	O60603

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 152184 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00470 AC: 1173 AN: 249672 AF XY: 0.00364

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00105 AC: 1534 AN: 1461194 Hom.: 31 Cov.: 35 AF XY: 0.000923 AC XY: 671 AN XY: 726828

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0278 AC: 1240 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 107 AN: 26126

East Asian (EAS) AF: 0.00219 AC: 87 AN: 39686

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111862

Other (OTH) AF: 0.000928 AC: 56 AN: 60368

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152302 Hom.: 5 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74478

African (AFR) AF: 0.000216 AC: 9 AN: 41574

American (AMR) AF: 0.00987 AC: 151 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000789 Hom.: 4

Bravo AF: 0.00311

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TLR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.33
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.18
Sift	Benign	0.036	D
Sift4G	Benign	0.082	T
Varity_R		0.16
gMVP		0.23
Mutation Taster		=94/6	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5743699;

hg19: chr4-154625291;