Genetic Variant TLR4:c.*3284C>A (chr9-117717932-C-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.*3284C>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 0.142 in 152,054 control chromosomes in the GnomAD database, including 1,682 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 0.14 ( 1682 hom., cov: 32)

Exomes 𝑓: 0.15 ( 0 hom. )

Consequence

TLR4
NM_138554.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.196

Publications

39 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=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5 link	c.*3284C>A	3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1	O00206-1
TLR4	NM_003266.4 link	c.*3284C>A	3_prime_UTR_variant	Exon 4 of 4		NP_003257.1	O00206-2
TLR4	NM_138557.3 link	c.*3284C>A	3_prime_UTR_variant	Exon 2 of 2		NP_612567.1	O00206-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8 link	c.*3284C>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5		O00206-1
ENSG00000285082	ENST00000697666.1 link	c.140+9203C>A		intron_variant	Intron 3 of 4			ENSP00000513391.1		A0A8V8TMK6

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21531

AN:

151916

Hom.:

1674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0848

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.126

GnomAD4 exome

AF:

0.150

AC:

AN:

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.188

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.142

AC:

21570

AN:

152034

Hom.:

1682

Cov.:

AF XY:

0.138

AC XY:

10279

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.205

AC:

8515

AN:

41460

American (AMR)

AF:

0.104

AC:

1590

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

470

AN:

3472

East Asian (EAS)

AF:

0.106

AC:

551

AN:

5174

South Asian (SAS)

AF:

0.104

AC:

503

AN:

4820

European-Finnish (FIN)

AF:

0.0848

AC:

896

AN:

10566

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8660

AN:

67958

Other (OTH)

AF:

0.130

AC:

275

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

925

1850

2776

3701

4626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.131

Hom.:

300

Bravo

AF:

0.145

Asia WGS

AF:

0.117

AC:

408

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.99

(source)

DANN

Benign

0.23

PhyloP100

0.20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over