Genetic Variant TLR9:p.Pro545Pro (chr3-52222681-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_017442.4(TLR9):c.1635G>A(p.Pro545Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,612,878 control chromosomes in the GnomAD database, including 214,754 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.

Frequency

Genomes: 𝑓 0.47 ( 17292 hom., cov: 34)

Exomes 𝑓: 0.52 ( 197462 hom. )

Consequence

TLR9
NM_017442.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.75

Publications

331 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.019).

BP7

Synonymous conserved (PhyloP=-5.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR9	NM_017442.4 link	c.1635G>A	p.Pro545Pro	synonymous_variant	Exon 2 of 2	ENST00000360658.3	NP_059138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR9	ENST00000360658.3 link	c.1635G>A	p.Pro545Pro	synonymous_variant	Exon 2 of 2	1	NM_017442.4	ENSP00000353874.2
ENSG00000173366	ENST00000494383.1 link	c.2094G>A	p.Pro698Pro	synonymous_variant	Exon 5 of 5	2		ENSP00000417517.1

Frequencies

GnomAD3 genomes

AF:

0.466

AC:

70882

AN:

152002

Hom.:

17291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.333

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.550

Gnomad EAS

AF:

0.386

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.477

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.539

Gnomad OTH

AF:

0.490

GnomAD2 exomes

AF:

0.495

AC:

123979

AN:

250650

AF XY:

0.495

show subpopulations

Gnomad AFR exome

AF:

0.335

Gnomad AMR exome

AF:

0.526

Gnomad ASJ exome

AF:

0.551

Gnomad EAS exome

AF:

0.370

Gnomad FIN exome

AF:

0.491

Gnomad NFE exome

AF:

0.544

Gnomad OTH exome

AF:

0.510

GnomAD4 exome

AF:

0.518

AC:

756250

AN:

1460758

Hom.:

197462

Cov.:

AF XY:

0.515

AC XY:

374401

AN XY:

726468

show subpopulations

African (AFR)

AF:

0.337

AC:

11288

AN:

33464

American (AMR)

AF:

0.522

AC:

23349

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14471

AN:

26134

East Asian (EAS)

AF:

0.439

AC:

17412

AN:

39652

South Asian (SAS)

AF:

0.416

AC:

35871

AN:

86246

European-Finnish (FIN)

AF:

0.494

AC:

26278

AN:

53210

Middle Eastern (MID)

AF:

0.497

AC:

2863

AN:

5766

European-Non Finnish (NFE)

AF:

0.536

AC:

595156

AN:

1111252

Other (OTH)

AF:

0.490

AC:

29562

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

24188

48376

72565

96753

120941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16800

33600

50400

67200

84000

<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:

0.466

AC:

70899

AN:

152120

Hom.:

17292

Cov.:

AF XY:

0.462

AC XY:

34390

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.332

AC:

13793

AN:

41490

American (AMR)

AF:

0.508

AC:

7762

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

1906

AN:

3468

East Asian (EAS)

AF:

0.386

AC:

1997

AN:

5174

South Asian (SAS)

AF:

0.419

AC:

2019

AN:

4824

European-Finnish (FIN)

AF:

0.477

AC:

5046

AN:

10574

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.539

AC:

36627

AN:

67980

Other (OTH)

AF:

0.492

AC:

1040

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1959

3918

5878

7837

9796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

648

1296

1944

2592

3240

<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:

0.513

Hom.:

26191

Bravo

AF:

0.464

Asia WGS

AF:

0.411

AC:

1431

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.063

(source)

DANN

Benign

0.47

PhyloP100

-5.7

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over