3-52221728-C-T

Position:

• chr3-52221728-C-T

Variant summary

Our verdict is Benign. Variant got -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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

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/exons	MANE	Protein	UniProt
TLR9	NM_017442.4	c.2588G>A	p.Arg863Gln	missense_variant	2/2	ENST00000360658.3	NP_059138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR9	ENST00000360658.3	c.2588G>A	p.Arg863Gln	missense_variant	2/2	1	NM_017442.4	ENSP00000353874.2
ENSG00000173366	ENST00000494383.1	c.3047G>A	p.Arg1016Gln	missense_variant	5/5	2		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

GnomAD3 exomes AF: 0.00826 AC: 2072 AN: 250958 Hom.: 30 AF XY: 0.00867 AC XY: 1178 AN XY: 135822

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

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.: 33 Cov.: 33 AF XY: 0.0122 AC XY: 907 AN XY: 74482

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.: 14

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Other links and lift over

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