dbSNP rs5744080: TLR8:p.His215Gln (chrX-12919685-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_138636.5(TLR8):c.645C>G(p.His215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,207,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

TLR8
NM_138636.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.52

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 Likely_benign. Variant got -3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5 link	c.645C>G	p.His215Gln	missense_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1	Q9NR97-1
TLR8	NM_016610.4 link	c.699C>G	p.His233Gln	missense_variant	Exon 3 of 3		NP_057694.2	Q9NR97-2
TLR8-AS1	NR_030727.1 link	n.241-11352G>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.645C>G	p.His215Gln	missense_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7		Q9NR97-1
TLR8	ENST00000311912.5 link	c.699C>G	p.His233Gln	missense_variant	Exon 3 of 3	1		ENSP00000312082.5		Q9NR97-2

Frequencies

GnomAD3 genomes

AF:

0.00000908

AC:

AN:

110135

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32353

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000549

AC:

AN:

182112

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

66926

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1097374

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000908

AC:

AN:

110135

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32353

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.014

DANN

Benign

0.57

DEOGEN2

Benign

0.086

T;.

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.60

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.015

Sift

Benign

0.30

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.035

B;.

Vest4

0.071

MutPred

0.23

Loss of ubiquitination at K219 (P = 0.1045);.;

MVP

0.093

MPC

0.76

ClinPred

0.073

GERP RS

-5.0

Varity_R

0.22

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.70

Position offset: 1

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