NM_017442.4:c.2588G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR9	NM_017442.4 link	c.2588G>A	p.Arg863Gln	missense_variant	Exon 2 of 2	ENST00000360658.3	NP_059138.1	Q9NR96-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR9	ENST00000360658.3 link	c.2588G>A	p.Arg863Gln	missense_variant	Exon 2 of 2	1	NM_017442.4	ENSP00000353874.2		Q9NR96-1
ENSG00000173366	ENST00000494383.1 link	c.3047G>A	p.Arg1016Gln	missense_variant	Exon 5 of 5	2		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

GnomAD3 exomes

AF:

0.00826

AC:

2072

AN:

250958

Hom.:

AF XY:

0.00867

AC XY:

1178

AN XY:

135822

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 SAS exome

AF:

0.0257

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

Gnomad4 AFR exome

AF:

0.0323

Gnomad4 AMR exome

AF:

0.00351

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.00219

Gnomad4 SAS exome

AF:

0.0257

Gnomad4 FIN exome

AF:

0.00158

Gnomad4 NFE exome

AF:

0.00525

Gnomad4 OTH exome

AF:

0.00760

GnomAD4 genome

AF:

0.0125

AC:

1902

AN:

152322

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

907

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0308

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00329

Gnomad4 SAS

AF:

0.0271

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00507

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00589

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

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 20, 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

0.073

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.0060

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over