dbSNP rs5744077: TLR8:p.Met10Val (chrX-12919068-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138636.5(TLR8):c.28A>G(p.Met10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,206,978 control chromosomes in the GnomAD database, including 320 homozygotes. There are 2,184 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.033 ( 178 hom., 979 hem., cov: 23)

Exomes 𝑓: 0.0040 ( 142 hom. 1205 hem. )

Consequence

TLR8
NM_138636.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.507

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017362535).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5 link	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1	Q9NR97-1
TLR8	NM_016610.4 link	c.82A>G	p.Met28Val	missense_variant	Exon 3 of 3		NP_057694.2	Q9NR97-2
TLR8-AS1	NR_030727.1 link	n.241-10735T>C		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7 link	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7		Q9NR97-1
TLR8	ENST00000311912.5 link	c.82A>G	p.Met28Val	missense_variant	Exon 3 of 3	1		ENSP00000312082.5		Q9NR97-2

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

3750

AN:

112078

Hom.:

178

Cov.:

AF XY:

0.0285

AC XY:

975

AN XY:

34256

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00852

Gnomad ASJ

AF:

0.00415

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0209

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.0224

GnomAD3 exomes

AF:

0.0103

AC:

1835

AN:

178640

Hom.:

AF XY:

0.00712

AC XY:

452

AN XY:

63444

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00224

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000225

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000825

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00401

AC:

4390

AN:

1094847

Hom.:

142

Cov.:

AF XY:

0.00334

AC XY:

1205

AN XY:

360649

show subpopulations

Gnomad4 AFR exome

AF:

0.118

Gnomad4 AMR exome

AF:

0.00524

Gnomad4 ASJ exome

AF:

0.00234

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000410

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000665

Gnomad4 OTH exome

AF:

0.00940

GnomAD4 genome

AF:

0.0334

AC:

3750

AN:

112131

Hom.:

178

Cov.:

AF XY:

0.0285

AC XY:

979

AN XY:

34319

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.00841

Gnomad4 ASJ

AF:

0.00415

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000364

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.0221

Alfa

AF:

0.00466

Hom.:

252

Bravo

AF:

0.0387

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.115

AC:

442

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.0112

AC:

1361

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.92

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.036

DANN

Benign

0.41

DEOGEN2

Benign

0.096

T;.

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.045

Sift

Benign

0.15

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0

B;.

Vest4

0.040

MPC

0.76

ClinPred

0.0012

GERP RS

0.30

Varity_R

0.064

gMVP

0.36

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over