9-117712651-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0210

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_benign. Variant got -6 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 criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.523A>G	p.Thr175Ala	missense_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.403A>G	p.Thr135Ala	missense_variant	4/4
TLR4	NM_138557.3	c.-78A>G		5_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.523A>G	p.Thr175Ala	missense_variant	3/3	1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.403A>G	p.Thr135Ala	missense_variant	4/4	1
TLR4	ENST00000472304.2	c.*257A>G		3_prime_UTR_variant	2/2	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

GnomAD3 exomes AF: 0.000651 AC: 163 AN: 250362 Hom.: 0 AF XY: 0.000665 AC XY: 90 AN XY: 135342

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 SAS exome AF: 0.000392

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.000373

Gnomad4 FIN exome AF: 0.00260

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000447

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00484

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000306 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: criteria provided, single submitter

Submissions by phenotype

TLR4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

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
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
MutationTaster	Benign	1.0	N;N
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

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

Other links and lift over

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