rs1927905

Variant names:

• chr9-117723030-T-C
• rs1927905
• NM_138554.5:c.*8382T>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.*8382T>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 0.0986 in 152,150 control chromosomes in the GnomAD database, including 1,197 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 0.099 (1197 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: -2.01
• Publications: 12 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*8382T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*8382T>C		3_prime_UTR_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3	c.*8382T>C		3_prime_UTR_variant	Exon 2 of 2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.*8382T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+14301T>C		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14977 AN: 152032 Hom.: 1195 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0978

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0904

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0986 AC: 15005 AN: 152150 Hom.: 1197 Cov.: 32 AF XY: 0.0957 AC XY: 7118 AN XY: 74402

African (AFR) AF: 0.223 AC: 9229 AN: 41442

American (AMR) AF: 0.0772 AC: 1181 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 339 AN: 3466

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5182

South Asian (SAS) AF: 0.0498 AC: 240 AN: 4824

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10618

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0511 AC: 3474 AN: 68002

Other (OTH) AF: 0.0942 AC: 199 AN: 2112

Alfa AF: 0.0651 Hom.: 284

Bravo AF: 0.108

Asia WGS AF: 0.0510 AC: 178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0060
DANN	Benign	0.20
PhyloP100		-2.0

Splicing

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

Other links and lift over

dbSNP: rs1927905; hg19: chr9-120485308;