rs5743820

chr4-38827207-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006068.5(TLR6):c.2267C>T(p.Thr756Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 1,614,166 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0078 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (165 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.841

Genes affected

TLR6 (HGNC:16711): (toll like receptor 6) 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. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor functionally interacts with toll-like receptor 2 to mediate cellular response to bacterial lipoproteins. A Ser249Pro polymorphism in the extracellular domain of the encoded protein may be associated with an increased of asthma is some populations.[provided by RefSeq, Jan 2011]

TLR1 (HGNC:11847): (toll like receptor 1) 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. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028704405).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00776 (1181/152284) while in subpopulation SAS AF= 0.0267 (129/4828). AF 95% confidence interval is 0.023. There are 5 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR6	NM_006068.5	c.2267C>T	p.Thr756Met	missense_variant	2/2	ENST00000508254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR6	ENST00000508254.6	c.2267C>T	p.Thr756Met	missense_variant	2/2	1	NM_006068.5	P1
TLR6	ENST00000381950.2	c.2267C>T	p.Thr756Met	missense_variant	3/3			P1
TLR1	ENST00000506146.5	c.-352-22014C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00779 AC: 1185 AN: 152166 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0286

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.00888

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0112 AC: 2824 AN: 251486 Hom.: 32 AF XY: 0.0132 AC XY: 1799 AN XY: 135914

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00760

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0312

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.00935 AC: 13673 AN: 1461882 Hom.: 165 Cov.: 31 AF XY: 0.0105 AC XY: 7666 AN XY: 727242

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.0265

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.00206

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.00776 AC: 1181 AN: 152284 Hom.: 5 Cov.: 33 AF XY: 0.00777 AC XY: 579 AN XY: 74476

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.0286

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00888

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0105 Hom.: 26

Bravo AF: 0.00758

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.0115 AC: 1395

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Uncertain	0.97
DEOGEN2	Benign	0.059	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.30	T;.;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.033	D;D;.
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.15	B;B;.
Vest4		0.030
MPC		0.19
ClinPred		0.0056	T
GERP RS		2.3
Varity_R		0.036
gMVP		0.17

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: rs5743820; hg19: chr4-38828828; COSMIC: COSV67935144; COSMIC: COSV67935144;