9-117712563-C-A
Variant names:
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.Pro145Pro) 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
NM_138554.5 synonymous
Scores
2
Clinical Significance
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]
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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 rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TLR4 | NM_138554.5 | c.435C>A | p.Pro145Pro | synonymous_variant | Exon 3 of 3 | ENST00000355622.8 | NP_612564.1 | |
| TLR4 | NM_003266.4 | c.315C>A | p.Pro105Pro | synonymous_variant | Exon 4 of 4 | NP_003257.1 | ||
| TLR4 | NM_138557.3 | c.-166C>A | 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.435C>A | p.Pro145Pro | synonymous_variant | Exon 3 of 3 | 1 | NM_138554.5 | ENSP00000363089.5 | ||
| ENSG00000285082 | ENST00000697666.1 | c.140+3834C>A | intron_variant | Intron 3 of 4 | ENSP00000513391.1 |
Frequencies
GnomAD3 genomes 0.00492 AC: 749AN: 152140Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00499 AC: 1252AN: 250934Hom.: 4 AF XY: 0.00510 AC XY: 692AN XY: 135612
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GnomAD4 exome AF: 0.00762 AC: 11140AN: 1461746Hom.: 52 Cov.: 32 AF XY: 0.00742 AC XY: 5399AN XY: 727166
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GnomAD4 genome 0.00493 AC: 750AN: 152258Hom.: 5 Cov.: 32 AF XY: 0.00461 AC XY: 343AN XY: 74448
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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
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided
- -
Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
TLR4: BP4, BP7, BS2 -
Jul 31, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
TLR4-related disorder Benign:1
Jul 03, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at