3-52221248-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_017442.4(TLR9):​c.3068G>A​(p.Arg1023Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,513,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1023W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TLR9
NM_017442.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.034182876).
BP6
Variant 3-52221248-C-T is Benign according to our data. Variant chr3-52221248-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3807411.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TLR9NM_017442.4 linkc.3068G>A p.Arg1023Gln 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
TLR9ENST00000360658.3 linkc.3068G>A p.Arg1023Gln missense_variant Exon 2 of 2 1 NM_017442.4 ENSP00000353874.2 Q9NR96-1
ENSG00000173366ENST00000494383.1 linkc.3527G>A p.Arg1176Gln missense_variant Exon 5 of 5 2 ENSP00000417517.1 H0Y858

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD3 exomes
AF:
0.0000113
AC:
2
AN:
176570
Hom.:
0
AF XY:
0.0000216
AC XY:
2
AN XY:
92776
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000232
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000117
AC:
16
AN:
1361732
Hom.:
0
Cov.:
30
AF XY:
0.0000120
AC XY:
8
AN XY:
666400
show subpopulations
Gnomad4 AFR exome
AF:
0.0000332
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000570
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000940
Gnomad4 OTH exome
AF:
0.0000179
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000335
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Feb 19, 2025
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
0.047
DANN
Benign
0.92
DEOGEN2
Benign
0.089
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.0085
N
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-0.64
N
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-0.49
N
REVEL
Benign
0.038
Sift
Benign
0.34
T
Sift4G
Benign
0.75
T
Polyphen
0.10
B
Vest4
0.15
MutPred
0.36
Gain of disorder (P = 0.1913);
MVP
0.32
MPC
0.55
ClinPred
0.039
T
GERP RS
-6.2
Varity_R
0.019
gMVP
0.53

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.

Other links and lift over

dbSNP: rs762518214; hg19: chr3-52255264; COSMIC: COSV100645646; COSMIC: COSV100645646; API