chr3-52221264-G-A

Variant names:

• chr3-52221264-G-A
• rs1351034672
• NM_017442.4:c.3052C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017442.4(TLR9):​c.3052C>T​(p.His1018Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,364,424 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1018N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TLR9 NM_017442.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14980093).

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.3052C>T	p.His1018Tyr	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.3052C>T	p.His1018Tyr	missense	Exon 2 of 2	ENSP00000353874.2	Q9NR96-1
	ENSG00000173366	ENST00000494383.1	TSL:2	c.3511C>T	p.His1171Tyr	missense	Exon 5 of 5	ENSP00000417517.1	H0Y858

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1364424 Hom.: 0 Cov.: 30 AF XY: 0.00000299 AC XY: 2 AN XY: 668088

African (AFR) AF: 0.00 AC: 0 AN: 30140

American (AMR) AF: 0.00 AC: 0 AN: 28794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19918

East Asian (EAS) AF: 0.00 AC: 0 AN: 38578

South Asian (SAS) AF: 0.00 AC: 0 AN: 70540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5304

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1065202

Other (OTH) AF: 0.00 AC: 0 AN: 56094

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.067
Sift	Benign	0.22	T
Sift4G	Uncertain	0.010	D
Polyphen		0.28	B
Vest4		0.14
MutPred		0.43		Loss of methylation at R1015 (P = 0.1042)
MVP		0.66
MPC		0.87
ClinPred		0.13	T
GERP RS		3.1
Varity_R		0.051
gMVP		0.58
Mutation Taster		=80/20	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: rs1351034672; hg19: chr3-52255280;