NM_138554.5:c.523A>G

Variant names:

• chr9-117712651-A-G
• rs16906079
• NM_138554.5:c.523A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138554.5(TLR4):​c.523A>G​(p.Thr175Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,613,610 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (6 hom.)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0210
• Publications: 16 publications found

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]

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062856674).
• BP6: Variant 9-117712651-A-G is Benign according to our data. Variant chr9-117712651-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3033547.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.523A>G	p.Thr175Ala	missense_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.403A>G	p.Thr135Ala	missense_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3	c.-78A>G		5_prime_UTR_variant	Exon 2 of 2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.523A>G	p.Thr175Ala	missense_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+3922A>G		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000651 AC: 163 AN: 250362 AF XY: 0.000665

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000517 AC: 755 AN: 1461362 Hom.: 6 Cov.: 32 AF XY: 0.000515 AC XY: 374 AN XY: 726872

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0104 AC: 411 AN: 39686

South Asian (SAS) AF: 0.000373 AC: 32 AN: 85844

European-Finnish (FIN) AF: 0.00260 AC: 139 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000128 AC: 142 AN: 1111972

Other (OTH) AF: 0.000447 AC: 27 AN: 60374

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00484 AC: 25 AN: 5170

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4808

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000439 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000577 AC: 70

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TLR4-related disorder Benign:1

Jun 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.15
DANN	Benign	0.58
DEOGEN2	Benign	0.12	.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.063	N
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	.;L;L
PhyloP100		-0.021
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.95	N;.;N
REVEL	Benign	0.042
Sift	Benign	0.16	T;.;T
Sift4G	Benign	0.26	T;.;T
Polyphen		0.019	.;B;B
Vest4		0.082
MVP		0.28
MPC		0.089
ClinPred		0.014	T
GERP RS		-7.9
Varity_R		0.090
gMVP		0.12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs16906079; hg19: chr9-120474929; COSMIC: COSV105915035;