3-52222681-C-T

Variant names:

• chr3-52222681-C-T
• rs352140
• NM_017442.4:c.1635G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_017442.4(TLR9):​c.1635G>A​(p.Pro545Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,612,878 control chromosomes in the GnomAD database, including 214,754 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17292 hom., cov: 34)
  • Exomes 𝑓: 0.52 (197462 hom.)
• Consequence: TLR9 NM_017442.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.75
• Publications: 331 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.019).
• BP7: Synonymous conserved (PhyloP=-5.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

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.1635G>A	p.Pro545Pro	synonymous	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.1635G>A	p.Pro545Pro	synonymous	Exon 2 of 2	ENSP00000353874.2
	ENSG00000173366	ENST00000494383.1	TSL:2	c.2094G>A	p.Pro698Pro	synonymous	Exon 5 of 5	ENSP00000417517.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70882 AN: 152002 Hom.: 17291 Cov.: 34

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.490

GnomAD2 exomes AF: 0.495 AC: 123979 AN: 250650 AF XY: 0.495

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.526

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.370

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.518 AC: 756250 AN: 1460758 Hom.: 197462 Cov.: 77 AF XY: 0.515 AC XY: 374401 AN XY: 726468

African (AFR) AF: 0.337 AC: 11288 AN: 33464

American (AMR) AF: 0.522 AC: 23349 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14471 AN: 26134

East Asian (EAS) AF: 0.439 AC: 17412 AN: 39652

South Asian (SAS) AF: 0.416 AC: 35871 AN: 86246

European-Finnish (FIN) AF: 0.494 AC: 26278 AN: 53210

Middle Eastern (MID) AF: 0.497 AC: 2863 AN: 5766

European-Non Finnish (NFE) AF: 0.536 AC: 595156 AN: 1111252

Other (OTH) AF: 0.490 AC: 29562 AN: 60332

GnomAD4 genome AF: 0.466 AC: 70899 AN: 152120 Hom.: 17292 Cov.: 34 AF XY: 0.462 AC XY: 34390 AN XY: 74374

African (AFR) AF: 0.332 AC: 13793 AN: 41490

American (AMR) AF: 0.508 AC: 7762 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1906 AN: 3468

East Asian (EAS) AF: 0.386 AC: 1997 AN: 5174

South Asian (SAS) AF: 0.419 AC: 2019 AN: 4824

European-Finnish (FIN) AF: 0.477 AC: 5046 AN: 10574

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36627 AN: 67980

Other (OTH) AF: 0.492 AC: 1040 AN: 2114

Alfa AF: 0.513 Hom.: 26191

Bravo AF: 0.464

Asia WGS AF: 0.411 AC: 1431 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.063
DANN	Benign	0.47
PhyloP100		-5.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs352140; hg19: chr3-52256697; COSMIC: COSV62347173; COSMIC: COSV62347173;