4-153703557-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001318789.2(TLR2):c.650T>C(p.Phe217Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,614,148 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (23 hom.)
• Consequence: TLR2 NM_001318789.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.29

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006396055).
• BP6: Variant 4-153703557-T-C is Benign according to our data. Variant chr4-153703557-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 710730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR2	NM_001318789.2	c.650T>C	p.Phe217Ser	missense_variant	3/3	ENST00000642700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR2	ENST00000642700.2	c.650T>C	p.Phe217Ser	missense_variant	3/3		NM_001318789.2	P1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152244 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00406 AC: 1020 AN: 251172 Hom.: 7 AF XY: 0.00400 AC XY: 543 AN XY: 135770

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.00518

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00349 AC: 5104 AN: 1461786 Hom.: 23 Cov.: 35 AF XY: 0.00342 AC XY: 2485 AN XY: 727190

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152362 Hom.: 4 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74518

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.00403

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00335 Hom.: 1

Bravo AF: 0.00199

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00463 AC: 562

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TLR2: BP4, BS2 -

TLR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 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	0.27
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.80	T;.;.;.;T
MetaRNN	Benign	0.0064	T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
Polyphen		0.92	.;P;P;P;P
Vest4		0.16
MVP		0.98
MPC		0.46
ClinPred		0.031	T
GERP RS		3.9
Varity_R		0.52
gMVP		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: rs139227237; hg19: chr4-154624709;