9-117704533-G-C

Variant names:

• chr9-117704533-G-C
• rs112840323
• ENST00000394487.5:c.-180G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003266.4(TLR4):​c.-180G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TLR4 NM_003266.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018798023).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003266.4. 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.61G>C	p.Val21Leu	missense	Exon 1 of 3	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.-180G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.-373G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_612567.1	O00206-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000394487.5	TSL:1	c.-180G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000377997.4	O00206-2
	ENSG00000285082	ENST00000697666.1		c.-180G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000513391.1	A0A8V8TMK6
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.61G>C	p.Val21Leu	missense	Exon 1 of 3	ENSP00000363089.5	O00206-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250310 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.8
DANN	Benign	0.74
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.092
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.043
MutPred		0.38		Gain of catalytic residue at V21 (P = 0.0441)
MVP		0.47
MPC		0.084
ClinPred		0.015	T
GERP RS		-2.0
PromoterAI		-0.053	Neutral
Varity_R		0.039
gMVP		0.21
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs112840323; hg19: chr9-120466811;