NM_016562.4:c.32A>T

Variant names:

• chrX-12885540-A-T
• rs179008
• NM_016562.4:c.32A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016562.4(TLR7):​c.32A>T​(p.Gln11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,202,693 control chromosomes in the GnomAD database, including 17,131 homozygotes. There are 75,300 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (1401 hom., 5934 hem., cov: 23)
  • Exomes 𝑓: 0.20 (15730 hom. 69366 hem.)
• Consequence: TLR7 NM_016562.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.150
• Publications: 197 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031428337).
• BP6: Variant X-12885540-A-T is Benign according to our data. Variant chrX-12885540-A-T is described in ClinVar as Benign. ClinVar VariationId is 2015182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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.32A>T	p.Gln11Leu	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.32A>T	p.Gln11Leu	missense	Exon 3 of 3	ENSP00000370034.3	Q9NYK1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 20199 AN: 111447 Hom.: 1402 Cov.: 23

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.0674

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.178 AC: 31777 AN: 178823 AF XY: 0.176

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.000145

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.198 AC: 216392 AN: 1091191 Hom.: 15730 Cov.: 29 AF XY: 0.194 AC XY: 69366 AN XY: 357607

African (AFR) AF: 0.126 AC: 3313 AN: 26241

American (AMR) AF: 0.192 AC: 6699 AN: 34896

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 3273 AN: 19186

East Asian (EAS) AF: 0.000332 AC: 10 AN: 30154

South Asian (SAS) AF: 0.0783 AC: 4182 AN: 53439

European-Finnish (FIN) AF: 0.270 AC: 10924 AN: 40444

Middle Eastern (MID) AF: 0.175 AC: 717 AN: 4099

European-Non Finnish (NFE) AF: 0.214 AC: 178955 AN: 836885

Other (OTH) AF: 0.181 AC: 8319 AN: 45847

GnomAD4 genome AF: 0.181 AC: 20191 AN: 111502 Hom.: 1401 Cov.: 23 AF XY: 0.176 AC XY: 5934 AN XY: 33704

African (AFR) AF: 0.127 AC: 3926 AN: 30794

American (AMR) AF: 0.209 AC: 2195 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 445 AN: 2638

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3584

South Asian (SAS) AF: 0.0665 AC: 179 AN: 2692

European-Finnish (FIN) AF: 0.269 AC: 1593 AN: 5912

Middle Eastern (MID) AF: 0.144 AC: 31 AN: 216

European-Non Finnish (NFE) AF: 0.215 AC: 11398 AN: 52952

Other (OTH) AF: 0.182 AC: 279 AN: 1533

Alfa AF: 0.200 Hom.: 5320

Bravo AF: 0.177

TwinsUK AF: 0.217 AC: 806

ALSPAC AF: 0.207 AC: 598

ESP6500AA AF: 0.136 AC: 521

ESP6500EA AF: 0.212 AC: 1429

ExAC AF: 0.174 AC: 21109

ClinVar

ClinVar submissions

Significance: Benign

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	0.12
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.79
DANN	Benign	0.94
DEOGEN2	Benign	0.082	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.67	N
PhyloP100		-0.15
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.036
Sift	Benign	0.094	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.68
ClinPred		0.012	T
GERP RS		-5.4
Varity_R		0.072
gMVP		0.50
Mutation Taster		=92/8	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: rs179008; hg19: chrX-12903659; COSMIC: COSV66123795;