Genetic Variant NM_138636.5:c.1953G>C (chrX-12920993-G-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_138636.5(TLR8):c.1953G>C(p.Leu651Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,097,489 control chromosomes in the GnomAD database, including 77,982 homozygotes. There are 163,025 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.58 ( 15140 hom., 18927 hem., cov: 23)

Exomes 𝑓: 0.45 ( 77982 hom. 163025 hem. )

Failed GnomAD Quality Control

Consequence

TLR8
NM_138636.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.61

Publications

49 publications found

Variant links:

Genes affected

TLR8 (HGNC:15632): (toll like receptor 8) 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. 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. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X. [provided by RefSeq, Jul 2008]

TLR8 links:

TLR8-AS1 (HGNC:40720): (TLR8 antisense RNA 1)

TLR8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant X-12920993-G-C is Benign according to our data. Variant chrX-12920993-G-C is described in ClinVar as Benign. ClinVar VariationId is 2687998.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.61 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TLR8	NM_138636.5 link	c.1953G>C	p.Leu651Leu	synonymous_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4 link	c.2007G>C	p.Leu669Leu	synonymous_variant	Exon 3 of 3		NP_057694.2
TLR8-AS1	NR_030727.1 link	n.241-12660C>G		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7 link	c.1953G>C	p.Leu651Leu	synonymous_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5 link	c.2007G>C	p.Leu669Leu	synonymous_variant	Exon 3 of 3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes

AF:

0.580

AC:

64079

AN:

110555

Hom.:

15138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.895

Gnomad AMI

AF:

0.487

Gnomad AMR

AF:

0.642

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.645

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.393

Gnomad OTH

AF:

0.575

GnomAD2 exomes

AF:

0.541

AC:

98712

AN:

182621

AF XY:

0.526

show subpopulations

Gnomad AFR exome

AF:

0.905

Gnomad AMR exome

AF:

0.687

Gnomad ASJ exome

AF:

0.469

Gnomad EAS exome

AF:

0.807

Gnomad FIN exome

AF:

0.431

Gnomad NFE exome

AF:

0.392

Gnomad OTH exome

AF:

0.500

GnomAD4 exome

AF:

0.445

AC:

488543

AN:

1097489

Hom.:

77982

Cov.:

AF XY:

0.449

AC XY:

163025

AN XY:

363003

show subpopulations

African (AFR)

AF:

0.906

AC:

23910

AN:

26389

American (AMR)

AF:

0.685

AC:

24103

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.467

AC:

9054

AN:

19381

East Asian (EAS)

AF:

0.810

AC:

24464

AN:

30194

South Asian (SAS)

AF:

0.641

AC:

34675

AN:

54126

European-Finnish (FIN)

AF:

0.437

AC:

17710

AN:

40519

Middle Eastern (MID)

AF:

0.495

AC:

2046

AN:

4131

European-Non Finnish (NFE)

AF:

0.392

AC:

329958

AN:

841499

Other (OTH)

AF:

0.491

AC:

22623

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

9771

19541

29312

39082

48853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11706

23412

35118

46824

58530

<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

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.580

AC:

64141

AN:

110608

Hom.:

15140

Cov.:

AF XY:

0.576

AC XY:

18927

AN XY:

32864

show subpopulations

African (AFR)

AF:

0.895

AC:

27196

AN:

30395

American (AMR)

AF:

0.643

AC:

6687

AN:

10406

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

1260

AN:

2638

East Asian (EAS)

AF:

0.804

AC:

2809

AN:

3492

South Asian (SAS)

AF:

0.644

AC:

1691

AN:

2627

European-Finnish (FIN)

AF:

0.415

AC:

2417

AN:

5826

Middle Eastern (MID)

AF:

0.514

AC:

109

AN:

212

European-Non Finnish (NFE)

AF:

0.393

AC:

20774

AN:

52834

Other (OTH)

AF:

0.578

AC:

870

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

781

1561

2342

3122

3903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.469

Hom.:

4913

Bravo

AF:

0.615

EpiCase

AF:

0.388

EpiControl

AF:

0.403

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 75% of patients studied by a panel of primary immunodeficiencies. Number of patients: 71. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.042

(source)

DANN

Benign

0.40

PhyloP100

-1.6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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