rs2302267

Variant names:

• chrX-12867459-T-G
• rs2302267
• NM_016562.4:c.-98-22T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016562.4(TLR7):​c.-98-22T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 604,443 control chromosomes in the GnomAD database, including 1,041 homozygotes. There are 13,252 hemizygotes in GnomAD. 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 0.054 (133 hom., 1895 hem., cov: 23)
  • Exomes 𝑓: 0.070 (908 hom. 11357 hem.)
• Consequence: TLR7 NM_016562.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.941
• Publications: 24 publications found

Genes affected

TLR7 (HGNC:15631): (toll like receptor 7) 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. The human TLR family comprises 11 members. 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. For the recognition of structural components in foreign microorganisms, the various TLRs exhibit different patterns of expression as well; in this way for example, TLR-3, -7, and -8 are essential in the recognition of single-stranded RNA viruses. TLR7 senses single-stranded RNA oligonucleotides containing guanosine- and uridine-rich sequences from RNA viruses, a recognition occuring in the endosomes of plasmacytoid dendritic cells and B cells. This gene is predominantly expressed in lung, placenta, and spleen, and is phylogenetically related and lies in close proximity to another family member, TLR8, on chromosome X. [provided by RefSeq, Aug 2020]

TLR7 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus 17

  Inheritance: XL Classification: MODERATE Submitted by: Baylor College of Medicine Research Center
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 74, COVID-19-related, X-linked

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR7	NM_016562.4	c.-98-22T>G		intron_variant	Intron 1 of 2	ENST00000380659.4	NP_057646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR7	ENST00000380659.4	c.-98-22T>G		intron_variant	Intron 1 of 2	1	NM_016562.4	ENSP00000370034.3
TLR7	ENST00000484204.1	n.-20T>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 6037 AN: 111874 Hom.: 133 Cov.: 23

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.0502

Gnomad NFE AF: 0.0630

Gnomad OTH AF: 0.0418

GnomAD4 exome AF: 0.0704 AC: 34675 AN: 492517 Hom.: 908 Cov.: 8 AF XY: 0.0763 AC XY: 11357 AN XY: 148921

African (AFR) AF: 0.0245 AC: 328 AN: 13369

American (AMR) AF: 0.0903 AC: 2213 AN: 24498

Ashkenazi Jewish (ASJ) AF: 0.0708 AC: 935 AN: 13207

East Asian (EAS) AF: 0.100 AC: 2669 AN: 26640

South Asian (SAS) AF: 0.112 AC: 3827 AN: 34215

European-Finnish (FIN) AF: 0.0740 AC: 2822 AN: 38160

Middle Eastern (MID) AF: 0.0754 AC: 219 AN: 2904

European-Non Finnish (NFE) AF: 0.0638 AC: 20033 AN: 314109

Other (OTH) AF: 0.0641 AC: 1629 AN: 25415

GnomAD4 genome AF: 0.0540 AC: 6043 AN: 111926 Hom.: 133 Cov.: 23 AF XY: 0.0556 AC XY: 1895 AN XY: 34090

African (AFR) AF: 0.0235 AC: 726 AN: 30831

American (AMR) AF: 0.0695 AC: 732 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 163 AN: 2645

East Asian (EAS) AF: 0.0778 AC: 277 AN: 3562

South Asian (SAS) AF: 0.108 AC: 293 AN: 2707

European-Finnish (FIN) AF: 0.0704 AC: 425 AN: 6036

Middle Eastern (MID) AF: 0.0459 AC: 10 AN: 218

European-Non Finnish (NFE) AF: 0.0631 AC: 3353 AN: 53179

Other (OTH) AF: 0.0413 AC: 63 AN: 1525

Alfa AF: 0.0605 Hom.: 3231

Bravo AF: 0.0531

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.43
PhyloP100		-0.94
PromoterAI		0.025	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2302267; hg19: chrX-12885578;