rs5743843

Variant names:

• chr3-52224079-A-C
• rs5743843
• NM_017442.4:c.237T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017442.4(TLR9):​c.237T>G​(p.His79Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,569,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TLR9 NM_017442.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.83
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044671834).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR9	NM_017442.4	MANE Select	c.237T>G	p.His79Gln	missense	Exon 2 of 2	NP_059138.1	Q9NR96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR9	ENST00000360658.3	TSL:1 MANE Select	c.237T>G	p.His79Gln	missense	Exon 2 of 2	ENSP00000353874.2	Q9NR96-1
	ENSG00000173366	ENST00000494383.1	TSL:2	c.696T>G	p.His232Gln	missense	Exon 5 of 5	ENSP00000417517.1	H0Y858
	ENSG00000173366	ENST00000478201.1	TSL:2	n.*244T>G		non_coding_transcript_exon	Exon 3 of 3	ENSP00000419980.1	H7C5I2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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

GnomAD2 exomes AF: 0.0000273 AC: 6 AN: 219442 AF XY: 0.0000256

Gnomad AFR exome AF: 0.000314

Gnomad AMR exome AF: 0.0000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1417110 Hom.: 0 Cov.: 36 AF XY: 0.00000286 AC XY: 2 AN XY: 698536

African (AFR) AF: 0.000123 AC: 4 AN: 32582

American (AMR) AF: 0.0000245 AC: 1 AN: 40824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23234

East Asian (EAS) AF: 0.00 AC: 0 AN: 39086

South Asian (SAS) AF: 0.00 AC: 0 AN: 79530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085832

Other (OTH) AF: 0.00 AC: 0 AN: 58480

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

African (AFR) AF: 0.000121 AC: 5 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000950 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.0
DANN	Benign	0.94
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.83	L
PhyloP100		-2.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.026
Sift	Benign	0.41	T
Sift4G	Benign	0.19	T
Polyphen		0.17	B
Vest4		0.17
MutPred		0.39		Loss of disorder (P = 0.1356)
MVP		0.49
MPC		0.57
ClinPred		0.025	T
GERP RS		-2.7
Varity_R		0.048
gMVP		0.70
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs5743843; hg19: chr3-52258095;