X-12885361-A-T

Variant names:

• chrX-12885361-A-T
• rs179009
• NM_016562.4:c.4-151A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016562.4(TLR7):​c.4-151A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 498,382 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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 0.00055 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.000054 (0 hom. 7 hem.)
• Consequence: TLR7 NM_016562.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 37 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Hemizygotes in GnomAd4 at 24 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR7	NM_016562.4	c.4-151A>T		intron_variant	Intron 2 of 2	ENST00000380659.4	NP_057646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR7	ENST00000380659.4	c.4-151A>T		intron_variant	Intron 2 of 2	1	NM_016562.4	ENSP00000370034.3

Frequencies

GnomAD3 genomes AF: 0.000528 AC: 59 AN: 111735 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000543 AC: 21 AN: 386590 Hom.: 0 AF XY: 0.0000595 AC XY: 7 AN XY: 117684

African (AFR) AF: 0.00167 AC: 19 AN: 11369

American (AMR) AF: 0.00 AC: 0 AN: 18746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10280

East Asian (EAS) AF: 0.00 AC: 0 AN: 25847

South Asian (SAS) AF: 0.00 AC: 0 AN: 22248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33041

Middle Eastern (MID) AF: 0.000714 AC: 1 AN: 1401

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 242181

Other (OTH) AF: 0.0000466 AC: 1 AN: 21477

GnomAD4 genome AF: 0.000546 AC: 61 AN: 111792 Hom.: 0 Cov.: 23 AF XY: 0.000707 AC XY: 24 AN XY: 33970

African (AFR) AF: 0.00191 AC: 59 AN: 30885

American (AMR) AF: 0.0000949 AC: 1 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5937

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53091

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.00 Hom.: 3670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.045
DANN	Benign	0.72
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs179009; hg19: chrX-12903480;