Genetic Variant TLR5:c.-438-845C>T (chr1-223138108-G-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_003268.6(TLR5):c.-438-845C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 150,804 control chromosomes in the GnomAD database, including 1,369 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 0.12 ( 1369 hom., cov: 26)

Consequence

TLR5
NM_003268.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.221

Publications

4 publications found

Variant links:

Genes affected

TLR5 (HGNC:11851): (toll like receptor 5) This gene encodes a member of the toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immune responses. These receptors recognize distinct pathogen-associated molecular patterns that are expressed on infectious agents. The protein encoded by this gene recognizes bacterial flagellin, the principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-kappaB, which in turn activates a host of inflammatory-related target genes. Mutations in this gene have been associated with both resistance and susceptibility to systemic lupus erythematosus, and susceptibility to Legionnaire disease.[provided by RefSeq, Dec 2009]

TLR5 Gene-Disease associations (from GenCC):

systemic lupus erythematosus, susceptibility to, 1
Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

TLR5 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 (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003268.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TLR5	NM_003268.6	MANE Select	c.-438-845C>T	intron	N/A	NP_003259.2
TLR5	NM_001437539.1		c.-532-845C>T	intron	N/A	NP_001424468.1	A0A2R8Y7Z4
TLR5	NM_001437624.1		c.-352-3244C>T	intron	N/A	NP_001424553.1	A0A2R8Y7Z4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TLR5	ENST00000642603.2	MANE Select	c.-438-845C>T	intron	N/A	ENSP00000496355.1	A0A2R8Y7Z4
TLR5	ENST00000407096.7	TSL:3	c.-352-3244C>T	intron	N/A	ENSP00000385458.3	B1AZ06
TLR5	ENST00000484766.2	TSL:3	c.-532-845C>T	intron	N/A	ENSP00000519510.1	O60602

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

17890

AN:

150684

Hom.:

1368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.144

Gnomad OTH

AF:

0.120

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.119

AC:

17898

AN:

150804

Hom.:

1369

Cov.:

AF XY:

0.121

AC XY:

8917

AN XY:

73580

show subpopulations

African (AFR)

AF:

0.0296

AC:

1215

AN:

41092

American (AMR)

AF:

0.184

AC:

2791

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

418

AN:

3464

East Asian (EAS)

AF:

0.267

AC:

1361

AN:

5090

South Asian (SAS)

AF:

0.128

AC:

608

AN:

4742

European-Finnish (FIN)

AF:

0.140

AC:

1437

AN:

10292

Middle Eastern (MID)

AF:

0.0651

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.144

AC:

9734

AN:

67696

Other (OTH)

AF:

0.121

AC:

253

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

708

1416

2124

2832

3540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.118

Hom.:

172

Bravo

AF:

0.119

Asia WGS

AF:

0.183

AC:

635

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.1

(source)

DANN

Benign

0.40

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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