rs7037117

Variant names:

• chr9-117721385-A-G
• rs7037117
• NM_138554.5:c.*6737A>G

Variant summary

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

The NM_138554.5(TLR4):​c.*6737A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 152,284 control chromosomes in the GnomAD database, including 14,941 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 0.39 (14941 hom., cov: 33)
  • Exomes 𝑓: 0.19 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.972
• Publications: 33 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 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.*6737A>G		3_prime_UTR	Exon 3 of 3	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.*6737A>G		3_prime_UTR	Exon 4 of 4	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.*6737A>G		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.*6737A>G		3_prime_UTR	Exon 3 of 3	ENSP00000363089.5	O00206-1
	ENSG00000285082	ENST00000697666.1		c.140+12656A>G		intron	N/A	ENSP00000513391.1	A0A8V8TMK6
	ENSG00000285082	ENST00000646089.2		c.93+16820A>G		intron	N/A	ENSP00000496197.1	A0A2R8YGN2

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59492 AN: 151994 Hom.: 14904 Cov.: 33

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.192 AC: 33 AN: 172 Hom.: 0 Cov.: 0 AF XY: 0.179 AC XY: 14 AN XY: 78

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.333 AC: 2 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2 AN: 4

East Asian (EAS) AF: 0.0667 AC: 2 AN: 30

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.278 AC: 5 AN: 18

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.200 AC: 20 AN: 100

Other (OTH) AF: 0.0833 AC: 1 AN: 12

GnomAD4 genome AF: 0.392 AC: 59596 AN: 152112 Hom.: 14941 Cov.: 33 AF XY: 0.389 AC XY: 28959 AN XY: 74362

African (AFR) AF: 0.721 AC: 29927 AN: 41482

American (AMR) AF: 0.309 AC: 4726 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1096 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1177 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1489 AN: 4816

European-Finnish (FIN) AF: 0.268 AC: 2839 AN: 10584

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17399 AN: 67984

Other (OTH) AF: 0.340 AC: 720 AN: 2116

Alfa AF: 0.316 Hom.: 14559

Bravo AF: 0.406

Asia WGS AF: 0.314 AC: 1089 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.47
DANN	Benign	0.51
PhyloP100		-0.97

Splicing

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

Other links and lift over

dbSNP: rs7037117; hg19: chr9-120483663;