NM_006068.5:c.1393G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006068.5(TLR6):c.1393G>A(p.Val465Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,613,944 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 160 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 146 hom. )

Consequence

TLR6
NM_006068.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.405

Publications

10 publications found

Variant links:

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]

TLR6 links:

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]

TLR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012029707).

BP6

Variant 4-38828081-C-T is Benign according to our data. Variant chr4-38828081-C-T is described in ClinVar as [Benign]. Clinvar id is 791975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR6	NM_006068.5 link	c.1393G>A	p.Val465Ile	missense_variant	Exon 2 of 2	ENST00000508254.6	NP_006059.2	Q9Y2C9-1B2R933

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TLR6	ENST00000508254.6 link	c.1393G>A	p.Val465Ile	missense_variant	Exon 2 of 2	1	NM_006068.5	ENSP00000424718.2	Q9Y2C9-1D6RAV7
TLR6	ENST00000381950.2 link	c.1393G>A	p.Val465Ile	missense_variant	Exon 3 of 3	6		ENSP00000371376.1	Q9Y2C9-1
TLR1	ENST00000506146.5 link	c.-352-22888G>A		intron_variant	Intron 1 of 5	4		ENSP00000423725.1	D6RCE8

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3554

AN:

152160

Hom.:

156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0771

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.0190

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.00830

AC:

2087

AN:

251366

AF XY:

0.00735

show subpopulations

Gnomad AFR exome

AF:

0.0755

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00571

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00383

AC:

5597

AN:

1461666

Hom.:

146

Cov.:

AF XY:

0.00395

AC XY:

2870

AN XY:

727158

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0788

AC:

2629

AN:

33374

American (AMR)

AF:

0.00389

AC:

174

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00501

AC:

199

AN:

39694

South Asian (SAS)

AF:

0.0166

AC:

1434

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000571

AC:

635

AN:

1111952

Other (OTH)

AF:

0.00795

AC:

480

AN:

60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

Heterozygous variant carriers

208

416

625

833

1041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0235

AC:

3574

AN:

152278

Hom.:

160

Cov.:

AF XY:

0.0239

AC XY:

1777

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0772

AC:

3207

AN:

41524

American (AMR)

AF:

0.00987

AC:

151

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00521

AC:

AN:

5184

South Asian (SAS)

AF:

0.0188

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68034

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

152

304

456

608

760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0979

Hom.:

3222

Bravo

AF:

0.0257

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00995

AC:

1208

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.1

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.042

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.55

T;.

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.7

N;N

PhyloP100

0.41

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.27

N;N

REVEL

Benign

0.018

Sift

Benign

1.0

T;T

Sift4G

Benign

0.97

T;T

Polyphen

0.0

B;B

Vest4

0.064

MVP

0.20

MPC

0.12

ClinPred

0.00040

GERP RS

2.6

Varity_R

0.012

gMVP

0.051

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over