Genetic Variant NM_138554.5:c.361G>A (chr9-117712489-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138554.5(TLR4):c.361G>A(p.Ala121Thr) 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. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A121S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.620

Publications

3 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 links:

ENSG00000285082 (HGNC:):

ENSG00000285082 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.072990656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5 link	c.361G>A	p.Ala121Thr	missense_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1	O00206-1
TLR4	NM_003266.4 link	c.241G>A	p.Ala81Thr	missense_variant	Exon 4 of 4		NP_003257.1	O00206-2
TLR4	NM_138557.3 link	c.-240G>A		5_prime_UTR_variant	Exon 2 of 2		NP_612567.1	O00206-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 link	c.361G>A	p.Ala121Thr	missense_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5		O00206-1
ENSG00000285082	ENST00000697666.1 link	c.140+3760G>A		intron_variant	Intron 3 of 4			ENSP00000513391.1		A0A8V8TMK6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.073

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;L

PhyloP100

0.62

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

N;.;N

REVEL

Benign

0.029

Sift

Benign

0.074

T;.;T

Sift4G

Benign

0.28

T;.;T

Polyphen

0.054

.;B;B

Vest4

0.097

MutPred

0.35

.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.71

MPC

0.14

ClinPred

0.25

GERP RS

3.2

Varity_R

0.26

gMVP

0.28

Mutation Taster

=54/46

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over