X-12886851-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_016562.4(TLR7):c.1343C>T(p.Ala448Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,208,256 control chromosomes in the GnomAD database, including 24 homozygotes. There are 1,602 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., 71 hem., cov: 23)

Exomes 𝑓: 0.0043 ( 23 hom. 1531 hem. )

Consequence

TLR7
NM_016562.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.592

Publications

28 publications found

Variant links:

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)

TLR7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049847364).

BP6

Variant X-12886851-C-T is Benign according to our data. Variant chrX-12886851-C-T is described in ClinVar as Benign. ClinVar VariationId is 787154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 71 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR7	NM_016562.4 link	c.1343C>T	p.Ala448Val	missense_variant	Exon 3 of 3	ENST00000380659.4	NP_057646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR7	ENST00000380659.4 link	c.1343C>T	p.Ala448Val	missense_variant	Exon 3 of 3	1	NM_016562.4	ENSP00000370034.3

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

317

AN:

111780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00468

Gnomad OTH

AF:

0.00532

GnomAD2 exomes

AF:

0.00290

AC:

525

AN:

181053

AF XY:

0.00270

show subpopulations

Gnomad AFR exome

AF:

0.000479

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.000539

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00465

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00429

AC:

4708

AN:

1096425

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

1531

AN XY:

361869

show subpopulations

African (AFR)

AF:

0.000569

AC:

AN:

26376

American (AMR)

AF:

0.00322

AC:

113

AN:

35102

Ashkenazi Jewish (ASJ)

AF:

0.000671

AC:

AN:

19362

East Asian (EAS)

AF:

0.00

AC:

AN:

30171

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53799

European-Finnish (FIN)

AF:

0.00195

AC:

AN:

40507

Middle Eastern (MID)

AF:

0.000968

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00514

AC:

4322

AN:

840930

Other (OTH)

AF:

0.00350

AC:

161

AN:

46044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

189

379

568

758

947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00283

AC:

317

AN:

111831

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

AN XY:

34053

show subpopulations

African (AFR)

AF:

0.000617

AC:

AN:

30806

American (AMR)

AF:

0.00295

AC:

AN:

10523

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00167

AC:

AN:

6004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00468

AC:

249

AN:

53189

Other (OTH)

AF:

0.00526

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00413

Hom.:

Bravo

AF:

0.00268

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00346

AC:

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.00402

AC:

ExAC

AF:

0.00314

AC:

381

EpiCase

AF:

0.00545

EpiControl

AF:

0.00462

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TLR7: BP4, BS1, BS2 -

TLR7-related disorder

Benign:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

PhyloP100

0.59

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.74

REVEL

Benign

0.029

Sift

Benign

0.32

Sift4G

Benign

0.29

Polyphen

0.023

Vest4

0.021

MVP

0.38

MPC

0.70

ClinPred

0.0018

GERP RS

3.1

Varity_R

0.067

gMVP

0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over