4-38828893-A-G

Position:

• chr4-38828893-A-G

Variant summary

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

The NM_006068.5(TLR6):​c.581T>C​(p.Leu194Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,611,972 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts 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 0.011 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (33 hom.)
• Consequence: TLR6 NM_006068.5 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003239423).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1643/152362) while in subpopulation AFR AF= 0.0372 (1548/41582). AF 95% confidence interval is 0.0357. There are 39 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR6	NM_006068.5	c.581T>C	p.Leu194Pro	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>C	p.Leu194Pro	missense_variant	2/2	1	NM_006068.5	ENSP00000424718.2
TLR6	ENST00000381950.2	c.581T>C	p.Leu194Pro	missense_variant	3/3	6		ENSP00000371376.1
TLR1	ENST00000506146.5	c.-352-23700T>C		intron_variant		4		ENSP00000423725.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1634 AN: 152244 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00296 AC: 734 AN: 247730 Hom.: 12 AF XY: 0.00211 AC XY: 284 AN XY: 134330

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000983

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00122 AC: 1784 AN: 1459610 Hom.: 33 Cov.: 33 AF XY: 0.00106 AC XY: 771 AN XY: 725970

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.0108 AC: 1643 AN: 152362 Hom.: 39 Cov.: 33 AF XY: 0.0101 AC XY: 755 AN XY: 74506

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.0122

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00381 AC: 463

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D;D;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.51	T;.;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.5	D;D;.
REVEL	Benign	0.023
Sift	Benign	0.047	D;D;.
Sift4G	Benign	0.068	T;T;T
Polyphen		0.25	B;B;.
Vest4		0.40
MVP		0.32
MPC		0.26
ClinPred		0.040	T
GERP RS		1.9
Varity_R		0.61
gMVP		0.80

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;