Genetic Variant NM_138554.5:c.*2808T>C (chr9-117717456-T-C) – 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.*2808T>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 0.162 in 152,122 control chromosomes in the GnomAD database, including 2,126 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 ( 2126 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

TLR4
NM_138554.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.08

Publications

6 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=-1.07).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TLR4	NM_138554.5 link	c.*2808T>C	3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4 link	c.*2808T>C	3_prime_UTR_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3 link	c.*2808T>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 link	c.*2808T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1 link	c.140+8727T>C		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

24587

AN:

152004

Hom.:

2116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0908

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.151

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:

24629

AN:

152122

Hom.:

2126

Cov.:

AF XY:

0.157

AC XY:

11695

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.216

AC:

8945

AN:

41490

American (AMR)

AF:

0.132

AC:

2011

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

701

AN:

3470

East Asian (EAS)

AF:

0.109

AC:

562

AN:

5168

South Asian (SAS)

AF:

0.119

AC:

574

AN:

4828

European-Finnish (FIN)

AF:

0.0908

AC:

963

AN:

10608

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.153

AC:

10414

AN:

67970

Other (OTH)

AF:

0.155

AC:

327

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1032

2064

3097

4129

5161

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:

0.127

AC:

441

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.36

(source)

DANN

Benign

0.26

PhyloP100

-3.1

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