X-12885639-A-G

Variant names:

• chrX-12885639-A-G
• rs1306830975
• NM_016562.4:c.131A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016562.4(TLR7):​c.131A>G​(p.Lys44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,098,251 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 4 hem.)
• Consequence: TLR7 NM_016562.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.75
• 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: PanelApp Australia, Baylor College of Medicine Research Center, ClinGen
• immunodeficiency 74, COVID-19-related, X-linked

  Inheritance: Unknown, XL Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.082366586).
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.131A>G	p.Lys44Arg	missense	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.131A>G	p.Lys44Arg	missense	Exon 3 of 3	ENSP00000370034.3	Q9NYK1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183229 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 14 AN: 1098251 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 4 AN XY: 363607

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

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

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 842133

Other (OTH) AF: 0.00 AC: 0 AN: 46097

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.2
DANN	Benign	0.95
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.11
Sift	Benign	0.032	D
Sift4G	Benign	0.23	T
Polyphen		0.0050	B
Vest4		0.050
MutPred		0.42		Loss of ubiquitination at K44 (P = 0.0127)
MVP		0.30
MPC		0.57
ClinPred		0.068	T
GERP RS		0.37
Varity_R		0.044
gMVP		0.49
Mutation Taster		=91/9	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: rs1306830975; hg19: chrX-12903758;