Genetic Variant TLR5:c.-5+59G>A (chr1-223132416-C-T) – 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.-5+59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 151,552 control chromosomes in the GnomAD database, including 33,152 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 0.65 ( 33152 hom., cov: 32)

Exomes 𝑓: 0.54 ( 19 hom. )

Failed GnomAD Quality Control

Consequence

TLR5
NM_003268.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.166

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:

Genome browser will be placed here

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=-1.02).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 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.-5+59G>A	intron	N/A	NP_003259.2
TLR5	NM_001437539.1		c.-5+59G>A	intron	N/A	NP_001424468.1	A0A2R8Y7Z4
TLR5	NM_001437624.1		c.-5+59G>A	intron	N/A	NP_001424553.1	A0A2R8Y7Z4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TLR5	ENST00000642603.2	MANE Select	c.-5+59G>A	intron	N/A	ENSP00000496355.1	A0A2R8Y7Z4
TLR5	ENST00000407096.7	TSL:3	c.-5+59G>A	intron	N/A	ENSP00000385458.3	B1AZ06
TLR5	ENST00000484766.2	TSL:3	c.-5+59G>A	intron	N/A	ENSP00000519510.1	O60602

Frequencies

GnomAD3 genomes

AF:

0.651

AC:

98615

AN:

151432

Hom.:

33116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.816

Gnomad AMI

AF:

0.496

Gnomad AMR

AF:

0.671

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.793

Gnomad SAS

AF:

0.573

Gnomad FIN

AF:

0.504

Gnomad MID

AF:

0.615

Gnomad NFE

AF:

0.569

Gnomad OTH

AF:

0.657

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.536

AC:

AN:

138

Hom.:

AF XY:

0.539

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.536

AC:

AN:

138

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:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.651

AC:

98707

AN:

151552

Hom.:

33152

Cov.:

AF XY:

0.649

AC XY:

48054

AN XY:

74072

show subpopulations

African (AFR)

AF:

0.816

AC:

33754

AN:

41362

American (AMR)

AF:

0.671

AC:

10204

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

2058

AN:

3452

East Asian (EAS)

AF:

0.793

AC:

4068

AN:

5132

South Asian (SAS)

AF:

0.572

AC:

2756

AN:

4818

European-Finnish (FIN)

AF:

0.504

AC:

5293

AN:

10500

Middle Eastern (MID)

AF:

0.621

AC:

180

AN:

290

European-Non Finnish (NFE)

AF:

0.569

AC:

38565

AN:

67778

Other (OTH)

AF:

0.657

AC:

1379

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1718

3435

5153

6870

8588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

770

1540

2310

3080

3850

<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:

0.470

Hom.:

1302

Bravo

AF:

0.675

Asia WGS

AF:

0.698

AC:

2426

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.1

(source)

DANN

Benign

0.33

PhyloP100

-0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over