rs5743842

chr3-52224303-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_017442.4(TLR9):c.13C>T(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,578,892 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (53 hom.)
• Consequence: TLR9 NM_017442.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.62

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TLR9
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021509826).
• BP6: Variant 3-52224303-G-A is Benign according to our data. Variant chr3-52224303-G-A is described in ClinVar as [Benign]. Clinvar id is 788970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1998/152222) while in subpopulation AFR AF= 0.0447 (1855/41524). AF 95% confidence interval is 0.043. There are 35 homozygotes in gnomad4. There are 956 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 35 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR9	NM_017442.4	c.13C>T	p.Arg5Cys	missense_variant	2/2	ENST00000360658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR9	ENST00000360658.3	c.13C>T	p.Arg5Cys	missense_variant	2/2	1	NM_017442.4	P1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1994 AN: 152104 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00360 AC: 677 AN: 187814 Hom.: 13 AF XY: 0.00266 AC XY: 268 AN XY: 100734

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000251

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00145 AC: 2062 AN: 1426670 Hom.: 53 Cov.: 36 AF XY: 0.00129 AC XY: 915 AN XY: 706964

Gnomad4 AFR exome AF: 0.0477

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000725

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.0131 AC: 1998 AN: 152222 Hom.: 35 Cov.: 33 AF XY: 0.0128 AC XY: 956 AN XY: 74430

Gnomad4 AFR AF: 0.0447

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00366 Hom.: 16

Bravo AF: 0.0159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0379 AC: 165

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00363 AC: 430

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.098
Dann	Benign	0.69
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.0020	B
Vest4		0.063
MVP		0.33
MPC		0.63
ClinPred		0.0018	T
GERP RS		-6.8
Varity_R		0.043
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs5743842; hg19: chr3-52258319; COSMIC: COSV59727043; COSMIC: COSV59727043;