rs5743845

Variant names:

• chr3-52221728-C-T
• rs5743845
• NM_017442.4:c.2588G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (98 hom.)
• Consequence: TLR9 NM_017442.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.66
• Publications: 22 publications found

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]

ENSG00000173366 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017442.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR9	NM_017442.4	MANE Select	c.2588G>A	p.Arg863Gln	missense	Exon 2 of 2	NP_059138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR9	ENST00000360658.3	TSL:1 MANE Select	c.2588G>A	p.Arg863Gln	missense	Exon 2 of 2	ENSP00000353874.2
	ENSG00000173366	ENST00000494383.1	TSL:2	c.3047G>A	p.Arg1016Gln	missense	Exon 5 of 5	ENSP00000417517.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1903 AN: 152204 Hom.: 33 Cov.: 33

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

GnomAD2 exomes AF: 0.00826 AC: 2072 AN: 250958 AF XY: 0.00867

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 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.: 98 Cov.: 30 AF XY: 0.00732 AC XY: 5325 AN XY: 727134

African (AFR) AF: 0.0323 AC: 1081 AN: 33478

American (AMR) AF: 0.00351 AC: 157 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26134

East Asian (EAS) AF: 0.00219 AC: 87 AN: 39700

South Asian (SAS) AF: 0.0257 AC: 2221 AN: 86256

European-Finnish (FIN) AF: 0.00158 AC: 84 AN: 53182

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00525 AC: 5840 AN: 1111996

Other (OTH) AF: 0.00760 AC: 459 AN: 60394

GnomAD4 genome AF: 0.0125 AC: 1902 AN: 152322 Hom.: 33 Cov.: 33 AF XY: 0.0122 AC XY: 907 AN XY: 74482

African (AFR) AF: 0.0308 AC: 1282 AN: 41580

American (AMR) AF: 0.00470 AC: 72 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00329 AC: 17 AN: 5172

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4832

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00507 AC: 345 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00769 Hom.: 26

Bravo AF: 0.0133

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00928 AC: 1127

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00533

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.0060
DANN	Benign	0.43
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-1.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.041
Sift	Benign	0.63	T
Sift4G	Benign	0.42	T
Polyphen		0.041	B
Vest4		0.079
MVP		0.26
MPC		0.54
ClinPred		0.030	T
GERP RS		-2.9
Varity_R		0.015
gMVP		0.67
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs5743845; hg19: chr3-52255744; COSMIC: COSV62346643; COSMIC: COSV62346643;