9-117712651-ACC-GCG

Variant names:

• chr9-117712651-ACC-GCG
• NM_138554.5:c.523_525delACCinsGCG
• TLR4 p.Thr175Ala

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_138554.5(TLR4):​c.523_525delACCinsGCG​(p.Thr175Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• Publications: 0 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]

TLR4 Gene-Disease associations (from GenCC):

• inflammatory bowel disease

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.523_525delACCinsGCG	p.Thr175Ala	missense	N/A	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.403_405delACCinsGCG	p.Thr135Ala	missense	N/A	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.-78_-76delACCinsGCG		5_prime_UTR	Exon 2 of 2	NP_612567.1	O00206-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.523_525delACCinsGCG	p.Thr175Ala	missense	N/A	ENSP00000363089.5	O00206-1
	TLR4	ENST00000394487.5	TSL:1	c.403_405delACCinsGCG	p.Thr135Ala	missense	N/A	ENSP00000377997.4	O00206-2
	TLR4	ENST00000472304.2	TSL:1	c.*257_*259delACCinsGCG		3_prime_UTR	Exon 2 of 2	ENSP00000496429.1	A0A2R8Y7P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-120474929;