X-12920335-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_Moderate PM2

The NM_138636.5(TLR8):c.1295C>T(p.Pro432Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. P432P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.46

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS1: Transcript NM_138636.5 (TLR8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR8	NM_138636.5	c.1295C>T	p.Pro432Leu	missense_variant	2/2	ENST00000218032.7
TLR8-AS1	NR_030727.1	n.241-12002G>A		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4	c.1349C>T	p.Pro450Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR8	ENST00000218032.7	c.1295C>T	p.Pro432Leu	missense_variant	2/2	1	NM_138636.5	P2
TLR8	ENST00000311912.5	c.1349C>T	p.Pro450Leu	missense_variant	3/3	1		A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 98 with autoinflammation, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2022

- -

INFLTR8 Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Megan Cooper Lab, Washington University School of Medicine in St Louis

-

We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects TLR8 protein function (PMID: 33512449). This variant has been observed in an apparently mosaic state in individual(s) with immunodeficiency and bone marrow failure (PMID: 33512449). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 432 of the TLR8 protein (p.Pro432Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.057	T;T
Polyphen		1.0	D;.
Vest4		0.41
MutPred		0.54		Loss of catalytic residue at P432 (P = 0.0306);.;
MVP		0.74
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-12938454; COSMIC: COSV54320272;