chrX-12885592-A-G

Variant names:

• chrX-12885592-A-G
• rs776821332
• NM_016562.4:c.84A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_016562.4(TLR7):​c.84A>G​(p.Arg28Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,209,690 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 5 hem.)
• Consequence: TLR7 NM_016562.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0900
• Publications: 0 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, ClinGen
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-12885592-A-G is Benign according to our data. Variant chrX-12885592-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2872719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.09 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 5 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016562.4. 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
	TLR7	NM_016562.4	MANE Select	c.84A>G	p.Arg28Arg	synonymous	Exon 3 of 3	NP_057646.1	B2R9N9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR7	ENST00000380659.4	TSL:1 MANE Select	c.84A>G	p.Arg28Arg	synonymous	Exon 3 of 3	ENSP00000370034.3	Q9NYK1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111932 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000755

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: 0.0000328 AC: 6 AN: 183168 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000802

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: 0.0000146 AC: 16 AN: 1097758 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 5 AN XY: 363120

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.000619 AC: 12 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841685

Other (OTH) AF: 0.0000651 AC: 3 AN: 46079

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111932 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34106

African (AFR) AF: 0.00 AC: 0 AN: 30836

American (AMR) AF: 0.00 AC: 0 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 2 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53185

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.000203 Hom.: 1

Bravo AF: 0.0000113

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs776821332; hg19: chrX-12903711;