dbSNP rs7037117: TLR4:c.*6737A>G (chr9-117721385-A-G) – 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.*6737A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 152,284 control chromosomes in the GnomAD database, including 14,941 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 0.39 ( 14941 hom., cov: 33)

Exomes 𝑓: 0.19 ( 0 hom. )

Consequence

TLR4
NM_138554.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.972

Publications

33 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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5 link	c.*6737A>G	3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1	O00206-1
TLR4	NM_003266.4 link	c.*6737A>G	3_prime_UTR_variant	Exon 4 of 4		NP_003257.1	O00206-2
TLR4	NM_138557.3 link	c.*6737A>G	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.*6737A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5		O00206-1
ENSG00000285082	ENST00000697666.1 link	c.140+12656A>G		intron_variant	Intron 3 of 4			ENSP00000513391.1		A0A8V8TMK6

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59492

AN:

151994

Hom.:

14904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.721

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.337

GnomAD4 exome

AF:

0.192

AC:

AN:

172

Hom.:

Cov.:

AF XY:

0.179

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.333

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.0667

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.278

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.200

AC:

AN:

100

Other (OTH)

AF:

0.0833

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.392

AC:

59596

AN:

152112

Hom.:

14941

Cov.:

AF XY:

0.389

AC XY:

28959

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.721

AC:

29927

AN:

41482

American (AMR)

AF:

0.309

AC:

4726

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1096

AN:

3470

East Asian (EAS)

AF:

0.228

AC:

1177

AN:

5168

South Asian (SAS)

AF:

0.309

AC:

1489

AN:

4816

European-Finnish (FIN)

AF:

0.268

AC:

2839

AN:

10584

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.256

AC:

17399

AN:

67984

Other (OTH)

AF:

0.340

AC:

720

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1579

3159

4738

6318

7897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.316

Hom.:

14559

Bravo

AF:

0.406

Asia WGS

AF:

0.314

AC:

1089

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.47

(source)

DANN

Benign

0.51

PhyloP100

-0.97

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over