rs5743845

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017442.4(TLR9):c.2588G>A(p.Arg863Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,613,954 control chromosomes in the GnomAD database, including 131 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 0.012 ( 33 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 98 hom. )

Consequence

TLR9
NM_017442.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.66

Publications

22 publications found

Variant links:

Genes affected

TLR9 (HGNC:15633): (toll like receptor 9) 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. Studies in mice and human indicate that this receptor mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response. [provided by RefSeq, Aug 2017]

TLR9 links:

ENSG00000173366 (HGNC:):

ENSG00000173366 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=0.0031407177).

BP6

Variant 3-52221728-C-T is Benign according to our data. Variant chr3-52221728-C-T is described in ClinVar as Benign. ClinVar VariationId is 776350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1902/152322) while in subpopulation AFR AF = 0.0308 (1282/41580). AF 95% confidence interval is 0.0294. There are 33 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017442.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR9	NM_017442.4	MANE Select	c.2588G>A	p.Arg863Gln	missense	Exon 2 of 2	NP_059138.1	Q9NR96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR9	ENST00000360658.3	TSL:1 MANE Select	c.2588G>A	p.Arg863Gln	missense	Exon 2 of 2	ENSP00000353874.2	Q9NR96-1
	ENSG00000173366	ENST00000494383.1	TSL:2	c.3047G>A	p.Arg1016Gln	missense	Exon 5 of 5	ENSP00000417517.1	H0Y858

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1903

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.00826

AC:

2072

AN:

250958

AF XY:

0.00867

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.00350

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00440

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00685

AC:

10010

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00732

AC XY:

5325

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0323

AC:

1081

AN:

33478

American (AMR)

AF:

0.00351

AC:

157

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26134

East Asian (EAS)

AF:

0.00219

AC:

AN:

39700

South Asian (SAS)

AF:

0.0257

AC:

2221

AN:

86256

European-Finnish (FIN)

AF:

0.00158

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00525

AC:

5840

AN:

1111996

Other (OTH)

AF:

0.00760

AC:

459

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

727

1453

2180

2906

3633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.0125

AC:

1902

AN:

152322

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

907

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0308

AC:

1282

AN:

41580

American (AMR)

AF:

0.00470

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00329

AC:

AN:

5172

South Asian (SAS)

AF:

0.0271

AC:

131

AN:

4832

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00507

AC:

345

AN:

68020

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00769

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.0352

AC:

155

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00928

AC:

1127

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00533

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.0060

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.083

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PhyloP100

-1.7

PrimateAI

Benign

0.32

PROVEAN

Benign

0.43

REVEL

Benign

0.041

Sift

Benign

0.63

Sift4G

Benign

0.42

Polyphen

0.041

Vest4

0.079

MVP

0.26

MPC

0.54

ClinPred

0.030

GERP RS

-2.9

Varity_R

0.015

gMVP

0.67

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over