9-117704494-G-T

Position:

chr9-117704494-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138554.5(TLR4):c.22G>T(p.Ala8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TLR4
NM_138554.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24319363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TLR4	NM_138554.5 linkuse as main transcript	c.22G>T	p.Ala8Ser	missense_variant	1/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 linkuse as main transcript	c.-219G>T		5_prime_UTR_variant	1/4		NP_003257.1
TLR4	NM_138557.3 linkuse as main transcript	c.-412G>T		5_prime_UTR_variant	1/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 linkuse as main transcript	c.22G>T	p.Ala8Ser	missense_variant	1/3	1	NM_138554.5	ENSP00000363089	P1	O00206-1
TLR4	ENST00000472304.2 linkuse as main transcript	c.22G>T	p.Ala8Ser	missense_variant	1/2	1		ENSP00000496429
TLR4	ENST00000394487.5 linkuse as main transcript	c.-219G>T		5_prime_UTR_variant	1/4	1		ENSP00000377997		O00206-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461394

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.22G>T (p.A8S) alteration is located in exon 1 (coding exon 1) of the TLR4 gene. This alteration results from a G to T substitution at nucleotide position 22, causing the alanine (A) at amino acid position 8 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

.;.;T;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

T;T;.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

.;.;M;M

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.35

.;.;.;N

REVEL

Benign

0.086

Sift

Uncertain

0.010

.;.;.;D

Sift4G

Uncertain

0.034

.;.;.;D

Polyphen

0.98

.;.;D;D

Vest4

0.17

MutPred

0.35

Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);

MVP

0.82

MPC

0.37

ClinPred

0.95

GERP RS

3.9

Varity_R

0.071

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over