rs35220466

chr4-38828734-C-T

Variant summary

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

The NM_006068.5(TLR6):c.740G>A(p.Arg247Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000863 in 1,613,838 control chromosomes in the GnomAD database, including 11 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (8 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.200

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=0.003818214).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000506 (739/1461528) while in subpopulation AFR AF= 0.0163 (546/33464). AF 95% confidence interval is 0.0152. There are 8 homozygotes in gnomad4_exome. There are 350 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR6	NM_006068.5	c.740G>A	p.Arg247Lys	missense_variant	2/2	ENST00000508254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR6	ENST00000508254.6	c.740G>A	p.Arg247Lys	missense_variant	2/2	1	NM_006068.5	P1
TLR6	ENST00000381950.2	c.740G>A	p.Arg247Lys	missense_variant	3/3			P1
TLR1	ENST00000506146.5	c.-352-23541G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 654 AN: 152192 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00111 AC: 278 AN: 250730 Hom.: 4 AF XY: 0.000833 AC XY: 113 AN XY: 135672

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1461528 Hom.: 8 Cov.: 33 AF XY: 0.000481 AC XY: 350 AN XY: 727020

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00429 AC: 654 AN: 152310 Hom.: 3 Cov.: 33 AF XY: 0.00428 AC XY: 319 AN XY: 74476

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.00489

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.0
Dann	Benign	0.58
DEOGEN2	Benign	0.037	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.66	T;.;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.67	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.61	N;N;.
REVEL	Benign	0.073
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.054
MVP		0.21
MPC		0.15
ClinPred		0.0044	T
GERP RS		3.6
Varity_R		0.022
gMVP		0.19

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: rs35220466; hg19: chr4-38830355;