9-117721498-G-T

Variant names:

• chr9-117721498-G-T
• rs752998
• NM_138554.5:c.*6850G>T

Variant summary

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

The NM_138554.5(TLR4):​c.*6850G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,068 control chromosomes in the GnomAD database, including 14,305 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 0.38 (14305 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.396
• Publications: 15 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]

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.713 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.*6850G>T		3_prime_UTR	Exon 3 of 3	NP_612564.1
	TLR4	NM_003266.4		c.*6850G>T		3_prime_UTR	Exon 4 of 4	NP_003257.1
	TLR4	NM_138557.3		c.*6850G>T		3_prime_UTR	Exon 2 of 2	NP_612567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.*6850G>T		3_prime_UTR	Exon 3 of 3	ENSP00000363089.5
	ENSG00000285082	ENST00000697666.1		c.140+12769G>T		intron	N/A	ENSP00000513391.1
	ENSG00000285082	ENST00000646089.2		c.93+16933G>T		intron	N/A	ENSP00000496197.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57112 AN: 151946 Hom.: 14268 Cov.: 33

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.324

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

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: 0.500 AC: 1 AN: 2

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: 0.376 AC: 57212 AN: 152064 Hom.: 14305 Cov.: 33 AF XY: 0.371 AC XY: 27611 AN XY: 74342

African (AFR) AF: 0.720 AC: 29843 AN: 41458

American (AMR) AF: 0.244 AC: 3723 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1085 AN: 3470

East Asian (EAS) AF: 0.151 AC: 785 AN: 5182

South Asian (SAS) AF: 0.301 AC: 1451 AN: 4824

European-Finnish (FIN) AF: 0.232 AC: 2447 AN: 10570

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16964 AN: 67980

Other (OTH) AF: 0.327 AC: 691 AN: 2112

Alfa AF: 0.175 Hom.: 430

Bravo AF: 0.387

Asia WGS AF: 0.274 AC: 950 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.0
DANN	Benign	0.43
PhyloP100		0.40

Splicing

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

Other links and lift over

dbSNP: rs752998; hg19: chr9-120483776;