Genetic Variant NM_003268.6:c.245C>T (chr1-223112787-G-A) – ACMG Classification: Benign (-16 pts)

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.245C>T(p.Thr82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,613,126 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 58 hom. )

Consequence

TLR5
NM_003268.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.53

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:

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=0.0050294697).

BP6

Variant 1-223112787-G-A is Benign according to our data. Variant chr1-223112787-G-A is described in ClinVar as Benign. ClinVar VariationId is 791521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6 link	c.245C>T	p.Thr82Ile	missense_variant	Exon 6 of 6	ENST00000642603.2	NP_003259.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR5	ENST00000642603.2 link	c.245C>T	p.Thr82Ile	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

643

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00632

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00595

AC:

1493

AN:

250876

AF XY:

0.00670

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000834

Gnomad NFE exome

AF:

0.00683

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00649

AC:

9486

AN:

1460856

Hom.:

Cov.:

AF XY:

0.00686

AC XY:

4982

AN XY:

726632

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33400

American (AMR)

AF:

0.00206

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

432

AN:

26052

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0141

AC:

1219

AN:

86180

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00642

AC:

7132

AN:

1111402

Other (OTH)

AF:

0.00706

AC:

426

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

600

1200

1801

2401

3001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.00424

AC:

646

AN:

152270

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

316

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41550

American (AMR)

AF:

0.00301

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0122

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00634

AC:

431

AN:

68030

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00695

Hom.:

Bravo

AF:

0.00406

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00586

AC:

711

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00889

EpiControl

AF:

0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.91

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.66

T;.;.;T

MetaRNN

Benign

0.0050

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.5

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.54

N;.;N;.

REVEL

Benign

0.020

Sift

Benign

0.12

T;.;T;.

Sift4G

Benign

0.27

T;.;T;.

Vest4

0.13

MVP

0.48

MPC

0.061

ClinPred

0.0014

GERP RS

3.1

gMVP

0.25

Mutation Taster

=94/6

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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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