Genetic Variant TLR4:c.*4471T>A (chr9-117719119-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0220

Publications

14 publications found

Variant links:

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 links:

ENSG00000285082 (HGNC:):

ENSG00000285082 links:

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ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TLR4	NM_138554.5	MANE Select	c.*4471T>A	3_prime_UTR	Exon 3 of 3	NP_612564.1
TLR4	NM_003266.4		c.*4471T>A	3_prime_UTR	Exon 4 of 4	NP_003257.1
TLR4	NM_138557.3		c.*4471T>A	3_prime_UTR	Exon 2 of 2	NP_612567.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TLR4	ENST00000355622.8	TSL:1 MANE Select	c.*4471T>A	3_prime_UTR	Exon 3 of 3	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1		c.140+10390T>A	intron	N/A	ENSP00000513391.1
ENSG00000285082	ENST00000646089.2		c.93+14554T>A	intron	N/A	ENSP00000496197.1

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

24580

AN:

152060

Hom.:

2125

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.162

AC:

24622

AN:

152178

Hom.:

2135

Cov.:

AF XY:

0.157

AC XY:

11687

AN XY:

74396

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.153

AC:

10417

AN:

68022

Other (OTH)

AF:

0.155

AC:

326

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1045

2089

3134

4178

5223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.1

(source)

DANN

Benign

0.49

PhyloP100

-0.022

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over