9-117712563-C-A

Position:

chr9-117712563-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_138554.5(TLR4):c.435C>A(p.Pro145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 1,614,004 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 52 hom. )

Consequence

TLR4
NM_138554.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0440

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 Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 9-117712563-C-A is Benign according to our data. Variant chr9-117712563-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 787708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.044 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TLR4	NM_138554.5 linkuse as main transcript	c.435C>A	p.Pro145=	synonymous_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 linkuse as main transcript	c.315C>A	p.Pro105=	synonymous_variant	4/4		NP_003257.1
TLR4	NM_138557.3 linkuse as main transcript	c.-166C>A		5_prime_UTR_variant	2/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 linkuse as main transcript	c.435C>A	p.Pro145=	synonymous_variant	3/3	1	NM_138554.5	ENSP00000363089	P1	O00206-1
TLR4	ENST00000394487.5 linkuse as main transcript	c.315C>A	p.Pro105=	synonymous_variant	4/4	1		ENSP00000377997		O00206-2
TLR4	ENST00000472304.2 linkuse as main transcript	c.*169C>A		3_prime_UTR_variant	2/2	1		ENSP00000496429

Frequencies

GnomAD3 genomes

AF:

0.00492

AC:

749

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00499

AC:

1252

AN:

250934

Hom.:

AF XY:

0.00510

AC XY:

692

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00776

Gnomad OTH exome

AF:

0.00557

GnomAD4 exome

AF:

0.00762

AC:

11140

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

5399

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00315

Gnomad4 ASJ exome

AF:

0.00651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00313

Gnomad4 FIN exome

AF:

0.00388

Gnomad4 NFE exome

AF:

0.00892

Gnomad4 OTH exome

AF:

0.00641

GnomAD4 genome

AF:

0.00493

AC:

750

AN:

152258

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00537

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00208

Gnomad4 NFE

AF:

0.00794

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00517

Hom.:

Bravo

AF:

0.00521

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.00687

EpiControl

AF:

0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TLR4: BP4, BP7, BS2 -

TLR4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as 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

BayesDel_noAF

Benign

-0.37

CADD

Benign

3.9

DANN

Benign

0.61

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