9-117708651-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138554.5(TLR4):c.182T>G(p.Leu61Arg) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

Genes affected

TLR4 (HGNC:11850): (toll like receptor 4) 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 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. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.182T>G	p.Leu61Arg	missense_variant	2/3	ENST00000355622.8
TLR4	NM_003266.4	c.62T>G	p.Leu21Arg	missense_variant	3/4
TLR4	NM_138557.3	c.-340-3738T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.182T>G	p.Leu61Arg	missense_variant	2/3	1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.62T>G	p.Leu21Arg	missense_variant	3/4	1
TLR4	ENST00000472304.2	c.94-3738T>G		intron_variant		1
TLR4	ENST00000490685.1	n.211T>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

TLR4: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	.;D;D
Vest4		0.95
MutPred		0.88		.;Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);
MVP		0.94
MPC		0.56
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.91

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: chr9-120470929;