NM_017442.4:c.13C>T

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.13C>T(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,578,892 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 53 hom. )

Consequence

TLR9
NM_017442.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.62

Publications

15 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=0.0021509826).

BP6

Variant 3-52224303-G-A is Benign according to our data. Variant chr3-52224303-G-A is described in ClinVar as Benign. ClinVar VariationId is 788970.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 = 0.0131 (1998/152222) while in subpopulation AFR AF = 0.0447 (1855/41524). AF 95% confidence interval is 0.043. There are 35 homozygotes in GnomAd4. There are 956 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR9	NM_017442.4 link	c.13C>T	p.Arg5Cys	missense_variant	Exon 2 of 2	ENST00000360658.3	NP_059138.1	Q9NR96-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TLR9	ENST00000360658.3 link	c.13C>T	p.Arg5Cys	missense_variant	Exon 2 of 2	1	NM_017442.4	ENSP00000353874.2	Q9NR96-1
ENSG00000173366	ENST00000494383.1 link	c.472C>T	p.Arg158Cys	missense_variant	Exon 5 of 5	2		ENSP00000417517.1	H0Y858
ENSG00000173366	ENST00000478201.1 link	n.*56-36C>T		intron_variant	Intron 2 of 2	2		ENSP00000419980.1	H7C5I2

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1994

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0447

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00714

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00360

AC:

677

AN:

187814

AF XY:

0.00266

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.00306

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000251

Gnomad OTH exome

AF:

0.00221

GnomAD4 exome

AF:

0.00145

AC:

2062

AN:

1426670

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

915

AN XY:

706964

show subpopulations

African (AFR)

AF:

0.0477

AC:

1551

AN:

32536

American (AMR)

AF:

0.00382

AC:

146

AN:

38210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25504

East Asian (EAS)

AF:

0.00

AC:

AN:

37386

South Asian (SAS)

AF:

0.0000725

AC:

AN:

82736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51352

Middle Eastern (MID)

AF:

0.00274

AC:

AN:

5106

European-Non Finnish (NFE)

AF:

0.000147

AC:

161

AN:

1094748

Other (OTH)

AF:

0.00311

AC:

184

AN:

59092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

101

202

303

404

505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0131

AC:

1998

AN:

152222

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

956

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0447

AC:

1855

AN:

41524

American (AMR)

AF:

0.00713

AC:

109

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67986

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00530

Hom.:

Bravo

AF:

0.0159

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0379

AC:

165

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00363

AC:

430

Asia WGS

AF:

0.00318

AC:

AN:

3478

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

0.096

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.098

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.16

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-2.6

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

REVEL

Benign

0.14

Sift

Benign

0.20

Sift4G

Uncertain

0.0040

Polyphen

0.0020

Vest4

0.063

MVP

0.33

MPC

0.63

ClinPred

0.0018

GERP RS

-6.8

Varity_R

0.043

gMVP

0.37

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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