X-12920755-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_138636.5(TLR8):c.1715G>T(p.Gly572Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G572D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.98

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_138636.5 (TLR8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a repeat LRR 16 (size 22) in uniprot entity TLR8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_138636.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-12920755-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1172678.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant X-12920755-G-T is Pathogenic according to our data. Variant chrX-12920755-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1339649.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR8	NM_138636.5	c.1715G>T	p.Gly572Val	missense_variant	2/2	ENST00000218032.7
TLR8-AS1	NR_030727.1	n.241-12422C>A		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4	c.1769G>T	p.Gly590Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR8	ENST00000218032.7	c.1715G>T	p.Gly572Val	missense_variant	2/2	1	NM_138636.5	P2
TLR8	ENST00000311912.5	c.1769G>T	p.Gly590Val	missense_variant	3/3	1		A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

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

- -

Autoimmune hemolytic anemia;C4015070:Systemic autoinflammation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics Facility, Ludwig-Maximilians-Universität München

Feb 08, 2022

The variant p.Gly572Val in TLR8 (Toll Like Receptor 8) was recently described as a loss-of-function variant for TLR8. Loss-of-function variants in TLR8 lead to X-linked recessive "severe autoimmune hemolytic anemia and autoinflammation" (Fejtkova et al. 2022; PMID: 34981838). Interestingly the variant p.Gly572Asp, at the same position but with negatively charged aspartate, is a gain-of-function variant for TLR8 in patients with X-linked recessive "immunodeficiency and bone marrow failure syndrome" (Aluri et al. 2021; PMID: 33512449). According to Fejtkova (2022), patients with “loss-of-function” in TLR8 are characterized by severe autoimmune anemia, which worsens due to infection, as well as autoinflammation in the form of fever, enteritis, arthritis and cerebral vasculitis. "Gain-of-function" variants are described according to Aluri (2021) with neutropenia, infections, lymphoproliferation, humoral immunodeficiency and, in some cases, bone marrow failure. The allele frequency database GnomAD (version v2.1.1), with mainly healthy subjects, does not yet list any heterozygous, homozygous or hemizyotic carriers of the variant p.Gly572Val. The protein encoded by TLR8, also called CD288, has 1059 amino acids and is a Toll-like receptor. This class of receptors functions as part of the innate immune response as so-called pattern-recognition receptors, i.e. they recognize structures of pathogens, such as specific RNA structures, which are not otherwise found in human cells. For example, it has been described for TLR8, an endosomal receptor, that it recognizes single-stranded RNA (ssRNA) of certain viruses and can support a corresponding immune response. The importance of the change in p.Gly572Val for the protein is predicted by the computer algorithms PolyPhen and SIFT as probably_damaging (0.999) and deleterious (0), respectively. The CADD score is 25.8 and thus an indication of a harmful change in the protein. This supports the clinical assessment by Fejtkova et al. 2022 as a loss-of-function variant. It seems plausible that the variant identified in our patient, p.Gly572Val, should have more of a destabilizing effect on the TLR8 dimer, since valine is a non-polar amino acid and therefore a loss-of -function is more likely. The variant in TLR8 is therefore the cause of our patient`s disease, and the variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.56		Loss of helix (P = 0.079);.;
MVP		0.62
MPC		2.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.97
gMVP		0.96

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-12938874;