Genetic Variant TLR4:p.Gln510His (chr9-117713658-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138554.5(TLR4):c.1530G>C(p.Gln510His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.482

Publications

26 publications found

Variant links:

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]

TLR4 Gene-Disease associations (from GenCC):

inflammatory bowel disease
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

TLR4 links:

ENSG00000285082 (HGNC:):

ENSG00000285082 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04446253).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR4	NM_138554.5	MANE Select	c.1530G>C	p.Gln510His	missense	Exon 3 of 3	NP_612564.1	O00206-1
TLR4	NM_003266.4		c.1410G>C	p.Gln470His	missense	Exon 4 of 4	NP_003257.1	O00206-2
TLR4	NM_138557.3		c.930G>C	p.Gln310His	missense	Exon 2 of 2	NP_612567.1	O00206-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR4	ENST00000355622.8	TSL:1 MANE Select	c.1530G>C	p.Gln510His	missense	Exon 3 of 3	ENSP00000363089.5	O00206-1
TLR4	ENST00000394487.5	TSL:1	c.1410G>C	p.Gln470His	missense	Exon 4 of 4	ENSP00000377997.4	O00206-2
TLR4	ENST00000472304.2	TSL:1	c.*1264G>C		3_prime_UTR	Exon 2 of 2	ENSP00000496429.1	A0A2R8Y7P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.16

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.23

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.59

M_CAP

Benign

0.0088

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.70

PhyloP100

-0.48

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.1

REVEL

Benign

0.0080

Sift

Benign

0.24

Sift4G

Benign

0.32

Polyphen

0.0030

Vest4

0.062

MutPred

0.25

Loss of helix (P = 0.0558)

MVP

0.21

MPC

0.084

ClinPred

0.047

GERP RS

-1.6

Varity_R

0.26

gMVP

0.19

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over