dbSNP rs5743843: TLR9:p.His79Gln (chr3-52224079-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017442.4(TLR9):c.237T>G(p.His79Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,569,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TLR9
NM_017442.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.83

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044671834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR9	NM_017442.4 link	c.237T>G	p.His79Gln	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.237T>G	p.His79Gln	missense_variant	Exon 2 of 2	1	NM_017442.4	ENSP00000353874.2	Q9NR96-1
ENSG00000173366	ENST00000494383.1 link	c.696T>G	p.His232Gln	missense_variant	Exon 5 of 5	2		ENSP00000417517.1	H0Y858
ENSG00000173366	ENST00000478201.1 link	n.*244T>G		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000419980.1	H7C5I2
ENSG00000173366	ENST00000478201.1 link	n.*244T>G		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000419980.1	H7C5I2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

219442

AF XY:

0.0000256

show subpopulations

Gnomad AFR exome

AF:

0.000314

Gnomad AMR exome

AF:

0.0000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000353

AC:

AN:

1417110

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

698536

show subpopulations

African (AFR)

AF:

0.000123

AC:

AN:

32582

American (AMR)

AF:

0.0000245

AC:

AN:

40824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23234

East Asian (EAS)

AF:

0.00

AC:

AN:

39086

South Asian (SAS)

AF:

0.00

AC:

AN:

79530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085832

Other (OTH)

AF:

0.00

AC:

AN:

58480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000329

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.605

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000950

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.0

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.059

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.67

M_CAP

Benign

0.011

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.83

PhyloP100

-2.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.78

REVEL

Benign

0.026

Sift

Benign

0.41

Sift4G

Benign

0.19

Polyphen

0.17

Vest4

0.17

MutPred

0.39

Loss of disorder (P = 0.1356);

MVP

0.49

MPC

0.57

ClinPred

0.025

GERP RS

-2.7

Varity_R

0.048

gMVP

0.70

Mutation Taster

=97/3

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

Computational scores

Splicing

Publications

Other links and lift over