rs7044464

Variant names:

• chr9-117719119-T-A
• rs7044464
• NM_138554.5:c.*4471T>A

Variant summary

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

The NM_138554.5(TLR4):​c.*4471T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,178 control chromosomes in the GnomAD database, including 2,135 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 0.16 (2135 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• Publications: 14 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*4471T>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*4471T>A		3_prime_UTR_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3	c.*4471T>A		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.*4471T>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+10390T>A		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24580 AN: 152060 Hom.: 2125 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0898

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.150

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 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) 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: 0.162 AC: 24622 AN: 152178 Hom.: 2135 Cov.: 32 AF XY: 0.157 AC XY: 11687 AN XY: 74396

African (AFR) AF: 0.216 AC: 8941 AN: 41478

American (AMR) AF: 0.132 AC: 2010 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3470

East Asian (EAS) AF: 0.110 AC: 568 AN: 5178

South Asian (SAS) AF: 0.119 AC: 574 AN: 4828

European-Finnish (FIN) AF: 0.0898 AC: 953 AN: 10610

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10417 AN: 68022

Other (OTH) AF: 0.155 AC: 326 AN: 2110

Alfa AF: 0.159 Hom.: 234

Bravo AF: 0.166

Asia WGS AF: 0.126 AC: 440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.49
PhyloP100		-0.022

Splicing

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

Other links and lift over

dbSNP: rs7044464; hg19: chr9-120481397;