9-117712563-C-A

Position:

• chr9-117712563-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0440

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 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	UniProt
TLR4	NM_138554.5	c.435C>A	p.Pro145=	synonymous_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.315C>A	p.Pro105=	synonymous_variant	4/4
TLR4	NM_138557.3	c.-166C>A		5_prime_UTR_variant	2/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 749 AN: 152140 Hom.: 5 Cov.: 32

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.: 4 AF XY: 0.00510 AC XY: 692 AN XY: 135612

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.: 52 Cov.: 32 AF XY: 0.00742 AC XY: 5399 AN XY: 727166

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.: 5 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74448

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.: 1

Bravo AF: 0.00521

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00687

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TLR4: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2018	- -

TLR4-related disorder Benign:1

Benign, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs5030711; hg19: chr9-120474841; COSMIC: COSV100790711; COSMIC: COSV100790711;