1-223111102-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003268.6(TLR5):c.1930A>T(p.Ile644Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00873 in 1,614,104 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 76 hom. )

Consequence

TLR5
NM_003268.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.82

Publications

23 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004293859).

BP6

Variant 1-223111102-T-A is Benign according to our data. Variant chr1-223111102-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 252618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6 link	c.1930A>T	p.Ile644Phe	missense_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.1930A>T	p.Ile644Phe	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1		A0A2R8Y7Z4

Frequencies

GnomAD3 genomes

AF:

0.00758

AC:

1153

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00969

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00520

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00929

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00702

AC:

1764

AN:

251166

AF XY:

0.00700

show subpopulations

Gnomad AFR exome

AF:

0.00537

Gnomad AMR exome

AF:

0.00567

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00624

Gnomad NFE exome

AF:

0.00927

Gnomad OTH exome

AF:

0.00881

GnomAD4 exome

AF:

0.00884

AC:

12927

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00867

AC XY:

6307

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00717

AC:

240

AN:

33478

American (AMR)

AF:

0.00577

AC:

258

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

428

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00249

AC:

215

AN:

86258

European-Finnish (FIN)

AF:

0.00601

AC:

321

AN:

53410

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00973

AC:

10815

AN:

1112008

Other (OTH)

AF:

0.00940

AC:

568

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

846

1691

2537

3382

4228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00762

AC:

1160

AN:

152226

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

591

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00575

AC:

239

AN:

41540

American (AMR)

AF:

0.00968

AC:

148

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00520

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00928

AC:

631

AN:

68012

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0100

Hom.:

Bravo

AF:

0.00795

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00668

AC:

811

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TLR5: BP4, BS2 -

not specified

Benign:1

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.044

(source)

DANN

Benign

0.95

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.61

T;.;.;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

-3.8

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.5

N;.;N;.

REVEL

Benign

0.057

Sift

Uncertain

0.0080

D;.;D;.

Sift4G

Uncertain

0.0060

D;.;D;.

Vest4

0.23

MVP

0.41

MPC

0.17

ClinPred

0.038

GERP RS

-3.5

gMVP

0.48

Mutation Taster

=100/0

polymorphism

(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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1-223111102-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over