rs5743809

Positions:

• chr4-38828893-A-C
• chr4-38828893-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000508254.6(TLR6):​c.581T>G​(p.Leu194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,612 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L194P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TLR6 ENST00000508254.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.740

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR6	NM_006068.5	c.581T>G	p.Leu194Arg	missense_variant	2/2	ENST00000508254.6	NP_006059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR6	ENST00000508254.6	c.581T>G	p.Leu194Arg	missense_variant	2/2	1	NM_006068.5	ENSP00000424718	P1
TLR6	ENST00000381950.2	c.581T>G	p.Leu194Arg	missense_variant	3/3			ENSP00000371376	P1
TLR1	ENST00000506146.5	c.-352-23700T>G		intron_variant		4		ENSP00000423725

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459612 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.000075	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Benign	0.094
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.79	T;.;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D;D;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.77
MutPred		0.34		Gain of disorder (P = 0.0244);Gain of disorder (P = 0.0244);Gain of disorder (P = 0.0244);
MVP		0.53
MPC		0.63
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.46
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: rs5743809; hg19: chr4-38830514;