Genetic Variant NM_003268.6:c.2523A>G (chr1-223110509-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_003268.6(TLR5):c.2523A>G(p.Lys841Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.09 in 1,614,048 control chromosomes in the GnomAD database, including 7,323 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 0.069 ( 451 hom., cov: 32)

Exomes 𝑓: 0.092 ( 6872 hom. )

Consequence

TLR5
NM_003268.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.457

Publications

18 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 links:

ENSG00000299361 (HGNC:):

ENSG00000299361 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP7

Synonymous conserved (PhyloP=0.457 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6 link	c.2523A>G	p.Lys841Lys	synonymous_variant	Exon 6 of 6	ENST00000642603.2	NP_003259.2	O60602A0A2R8Y7Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR5	ENST00000642603.2 link	c.2523A>G	p.Lys841Lys	synonymous_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1		A0A2R8Y7Z4

Frequencies

GnomAD3 genomes

AF:

0.0690

AC:

10500

AN:

152180

Hom.:

451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.0724

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0321

Gnomad FIN

AF:

0.0717

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.0927

GnomAD2 exomes

AF:

0.0744

AC:

18687

AN:

251192

AF XY:

0.0753

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.0522

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0802

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.0891

GnomAD4 exome

AF:

0.0922

AC:

134743

AN:

1461750

Hom.:

6872

Cov.:

AF XY:

0.0914

AC XY:

66458

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0150

AC:

502

AN:

33468

American (AMR)

AF:

0.0543

AC:

2425

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

3141

AN:

26132

East Asian (EAS)

AF:

0.000529

AC:

AN:

39686

South Asian (SAS)

AF:

0.0406

AC:

3503

AN:

86254

European-Finnish (FIN)

AF:

0.0790

AC:

4221

AN:

53412

Middle Eastern (MID)

AF:

0.0955

AC:

551

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115207

AN:

1111940

Other (OTH)

AF:

0.0856

AC:

5172

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

6726

13452

20178

26904

33630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4042

8084

12126

16168

20210

<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:

0.0689

AC:

10496

AN:

152298

Hom.:

451

Cov.:

AF XY:

0.0658

AC XY:

4900

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0189

AC:

786

AN:

41570

American (AMR)

AF:

0.0722

AC:

1105

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

377

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.0325

AC:

157

AN:

4826

European-Finnish (FIN)

AF:

0.0717

AC:

760

AN:

10604

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

6982

AN:

68018

Other (OTH)

AF:

0.0918

AC:

194

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

506

1012

1518

2024

2530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0934

Hom.:

394

Bravo

AF:

0.0675

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.112

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.1

(source)

DANN

Benign

0.54

PhyloP100

0.46

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over