rs5743699

Positions:

• chr4-153704139-C-T

Variant summary

Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 (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 id is 3053334.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 671 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR2	NM_001318789.2	c.1232C>T	p.Thr411Ile	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.1232C>T	p.Thr411Ile	missense_variant	3/3		NM_001318789.2	ENSP00000494425.1

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

GnomAD3 exomes AF: 0.00470 AC: 1173 AN: 249672 Hom.: 27 AF XY: 0.00364 AC XY: 492 AN XY: 135162

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 SAS exome AF: 0.0000991

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.00219

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000928

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

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000506 Hom.: 0

Bravo AF: 0.00311

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00381 AC: 463

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TLR2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 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
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;T;T;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;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	2.9	M;M;M;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	.;.;.;D
REVEL	Benign	0.18
Sift	Benign	0.036	.;.;.;D
Sift4G	Benign	0.082	.;.;.;T
Polyphen		0.96	P;P;P;P
Vest4		0.29
MVP		0.84
MPC		0.40
ClinPred		0.050	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.23

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: rs5743699; hg19: chr4-154625291;