NM_138554.5:c.*3189T>C

Variant names:

• chr9-117717837-T-C
• rs1927906
• NM_138554.5:c.*3189T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138554.5(TLR4):​c.*3189T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,008 control chromosomes in the GnomAD database, including 4,910 homozygotes. 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: 𝑓 0.20 (4910 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.370
• Publications: 40 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

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.*3189T>C		3_prime_UTR	Exon 3 of 3	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.*3189T>C		3_prime_UTR	Exon 4 of 4	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.*3189T>C		3_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.*3189T>C		3_prime_UTR	Exon 3 of 3	ENSP00000363089.5	O00206-1
	ENSG00000285082	ENST00000697666.1		c.140+9108T>C		intron	N/A	ENSP00000513391.1	A0A8V8TMK6
	ENSG00000285082	ENST00000646089.2		c.93+13272T>C		intron	N/A	ENSP00000496197.1	A0A2R8YGN2

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30170 AN: 151890 Hom.: 4903 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.161

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.199 AC: 30214 AN: 152008 Hom.: 4910 Cov.: 32 AF XY: 0.199 AC XY: 14776 AN XY: 74292

African (AFR) AF: 0.451 AC: 18680 AN: 41428

American (AMR) AF: 0.107 AC: 1627 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 373 AN: 3466

East Asian (EAS) AF: 0.0436 AC: 225 AN: 5158

South Asian (SAS) AF: 0.180 AC: 869 AN: 4818

European-Finnish (FIN) AF: 0.140 AC: 1483 AN: 10578

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0960 AC: 6527 AN: 67966

Other (OTH) AF: 0.161 AC: 339 AN: 2112

Alfa AF: 0.119 Hom.: 2342

Bravo AF: 0.204

Asia WGS AF: 0.139 AC: 483 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.9
DANN	Benign	0.80
PhyloP100		0.37

Splicing

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

Other links and lift over

dbSNP: rs1927906; hg19: chr9-120480115;