X-12919119-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138636.5(TLR8):c.79G>A(p.Glu27Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,210,065 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 40 hem. )

Consequence

TLR8
NM_138636.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.01

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:):

TLR8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020318747).

BP6

Variant X-12919119-G-A is Benign according to our data. Variant chrX-12919119-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2227243.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Hemizygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TLR8	NM_138636.5 linkuse as main transcript	c.79G>A	p.Glu27Lys	missense_variant	2/2	ENST00000218032.7
TLR8-AS1	NR_030727.1 linkuse as main transcript	n.241-10786C>T		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4 linkuse as main transcript	c.133G>A	p.Glu45Lys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR8	ENST00000218032.7 linkuse as main transcript	c.79G>A	p.Glu27Lys	missense_variant	2/2	1	NM_138636.5	P2	Q9NR97-1
TLR8	ENST00000311912.5 linkuse as main transcript	c.133G>A	p.Glu45Lys	missense_variant	3/3	1		A2	Q9NR97-2

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

111966

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

AN XY:

34134

show subpopulations

Gnomad AFR

AF:

0.000520

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000276

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000164

AC:

AN:

182900

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

67522

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000216

Gnomad SAS exome

AF:

0.000158

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000981

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

123

AN:

1098046

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

363410

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0000924

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000915

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000232

AC:

AN:

112019

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

34197

show subpopulations

Gnomad4 AFR

AF:

0.000519

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000277

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.79G>A (p.E27K) alteration is located in exon 2 (coding exon 2) of the TLR8 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the glutamic acid (E) at amino acid position 27 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

TLR8: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.76

Cadd

Benign

1.8

Dann

Benign

0.58

DEOGEN2

Benign

0.090

T;.

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.090

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.033

Sift

Benign

0.75

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.017

B;.

Vest4

0.053

MVP

0.18

MPC

0.84

ClinPred

0.0025

GERP RS

2.0

Varity_R

0.048

gMVP

0.23

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

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