rs3764880

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_138636.5(TLR8):c.1A>G(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,107,953 control chromosomes in the GnomAD database, including 35,042 homozygotes. There are 98,465 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.30 ( 4102 hom., 10375 hem., cov: 24)

Exomes 𝑓: 0.28 ( 30940 hom. 88090 hem. )

Consequence

TLR8
NM_138636.5 start_lost, splice_region

Scores

Splicing: ADA: 0.00004202

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.617

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant X-12906707-A-G is Benign according to our data. Variant chrX-12906707-A-G is described in ClinVar as [Benign]. Clinvar id is 2688133.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TLR8	NM_138636.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/2	ENST00000218032.7	NP_619542.1
TLR8-AS1	NR_030727.1 linkuse as main transcript	n.359-456T>C		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4 linkuse as main transcript	c.-83A>G		splice_region_variant, 5_prime_UTR_variant	1/3		NP_057694.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7 linkuse as main transcript	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/2	1	NM_138636.5	ENSP00000218032	P2	Q9NR97-1
TLR8	ENST00000311912.5 linkuse as main transcript	c.-83A>G		splice_region_variant, 5_prime_UTR_variant	1/3	1		ENSP00000312082	A2	Q9NR97-2
TLR8-AS1	ENST00000451564.1 linkuse as main transcript	n.119-456T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

33957

AN:

111550

Hom.:

4105

Cov.:

AF XY:

0.307

AC XY:

10345

AN XY:

33750

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.381

Gnomad AMR

AF:

0.455

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.807

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.199

Gnomad MID

AF:

0.349

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.341

GnomAD3 exomes

AF:

0.310

AC:

36412

AN:

117570

Hom.:

5255

AF XY:

0.300

AC XY:

10830

AN XY:

36126

show subpopulations

Gnomad AFR exome

AF:

0.251

Gnomad AMR exome

AF:

0.495

Gnomad ASJ exome

AF:

0.322

Gnomad EAS exome

AF:

0.799

Gnomad SAS exome

AF:

0.457

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.278

GnomAD4 exome

AF:

0.281

AC:

279874

AN:

996348

Hom.:

30940

Cov.:

AF XY:

0.280

AC XY:

88090

AN XY:

314368

show subpopulations

Gnomad4 AFR exome

AF:

0.256

Gnomad4 AMR exome

AF:

0.475

Gnomad4 ASJ exome

AF:

0.369

Gnomad4 EAS exome

AF:

0.791

Gnomad4 SAS exome

AF:

0.451

Gnomad4 FIN exome

AF:

0.210

Gnomad4 NFE exome

AF:

0.252

Gnomad4 OTH exome

AF:

0.324

GnomAD4 genome

AF:

0.305

AC:

33985

AN:

111605

Hom.:

4102

Cov.:

AF XY:

0.307

AC XY:

10375

AN XY:

33815

show subpopulations

Gnomad4 AFR

AF:

0.271

Gnomad4 AMR

AF:

0.455

Gnomad4 ASJ

AF:

0.408

Gnomad4 EAS

AF:

0.807

Gnomad4 SAS

AF:

0.530

Gnomad4 FIN

AF:

0.199

Gnomad4 NFE

AF:

0.254

Gnomad4 OTH

AF:

0.344

Alfa

AF:

0.294

Hom.:

30122

Bravo

AF:

0.329

TwinsUK

AF:

0.263

AC:

975

ALSPAC

AF:

0.244

AC:

705

ESP6500AA

AF:

0.264

AC:

1013

ESP6500EA

AF:

0.247

AC:

1664

ExAC

AF:

0.359

AC:

43348

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.027

DANN

Benign

0.24

DEOGEN2

Benign

0.098

FATHMM_MKL

Benign

0.0011

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0000015

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

P;P

PROVEAN

Benign

0.060

REVEL

Benign

0.11

Sift

Pathogenic

0.0

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.010

ClinPred

0.0039

GERP RS

-3.6

Varity_R

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000042

dbscSNV1_RF

Benign

0.022

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over