X-12885540-A-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR7	NM_016562.4	c.32A>T	p.Gln11Leu	missense_variant	3/3	ENST00000380659.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR7	ENST00000380659.4	c.32A>T	p.Gln11Leu	missense_variant	3/3	1	NM_016562.4	P1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 20199 AN: 111447 Hom.: 1402 Cov.: 23 AF XY: 0.176 AC XY: 5933 AN XY: 33639

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

GnomAD3 exomes AF: 0.178 AC: 31777 AN: 178823 Hom.: 2171 AF XY: 0.176 AC XY: 11187 AN XY: 63623

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 SAS exome AF: 0.0765

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

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.000332

Gnomad4 SAS exome AF: 0.0783

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.181

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

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.0665

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.182

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs179008; hg19: chrX-12903659; COSMIC: COSV66123795;