X-12889539-C-G

Variant names:

• chrX-12889539-C-G
• rs3853839
• NM_016562.4:c.*881C>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.*881C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 112,689 control chromosomes in the GnomAD database, including 2,614 homozygotes. There are 8,314 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 0.23 (2585 hom., 8253 hem., cov: 24)
  • Exomes 𝑓: 0.25 (29 hom. 61 hem.)
• Consequence: TLR7 NM_016562.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 134 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR7	NM_016562.4	c.*881C>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000380659.4	NP_057646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR7	ENST00000380659.4	c.*881C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_016562.4	ENSP00000370034.3

Frequencies

GnomAD3 genomes AF: 0.230 AC: 25661 AN: 111721 Hom.: 2586 Cov.: 24

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.246 AC: 227 AN: 922 Hom.: 29 Cov.: 0 AF XY: 0.270 AC XY: 61 AN XY: 226

African (AFR) AF: 0.348 AC: 8 AN: 23

American (AMR) AF: 0.563 AC: 9 AN: 16

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 13 AN: 32

East Asian (EAS) AF: 0.650 AC: 67 AN: 103

South Asian (SAS) AF: 0.500 AC: 2 AN: 4

European-Finnish (FIN) AF: 0.169 AC: 24 AN: 142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1

European-Non Finnish (NFE) AF: 0.168 AC: 94 AN: 558

Other (OTH) AF: 0.233 AC: 10 AN: 43

GnomAD4 genome AF: 0.230 AC: 25676 AN: 111767 Hom.: 2585 Cov.: 24 AF XY: 0.243 AC XY: 8253 AN XY: 33995

African (AFR) AF: 0.180 AC: 5556 AN: 30825

American (AMR) AF: 0.398 AC: 4222 AN: 10617

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 787 AN: 2648

East Asian (EAS) AF: 0.778 AC: 2758 AN: 3544

South Asian (SAS) AF: 0.525 AC: 1398 AN: 2665

European-Finnish (FIN) AF: 0.189 AC: 1130 AN: 5968

Middle Eastern (MID) AF: 0.298 AC: 65 AN: 218

European-Non Finnish (NFE) AF: 0.174 AC: 9235 AN: 53076

Other (OTH) AF: 0.258 AC: 394 AN: 1530

Alfa AF: 0.184 Hom.: 1083

Bravo AF: 0.249

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.27
DANN	Benign	0.70
PhyloP100		-1.0
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: rs3853839; hg19: chrX-12907658; COSMIC: COSV66125747;