1-223110495-T-C

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.2537A>G(p.Asp846Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00872 in 1,614,160 control chromosomes in the GnomAD database, including 81 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 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: -0.112

Publications

21 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:

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=0.0029380918).

BP6

Variant 1-223110495-T-C is Benign according to our data. Variant chr1-223110495-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR5	NM_003268.6	MANE Select	c.2537A>G	p.Asp846Gly	missense	Exon 6 of 6	NP_003259.2
TLR5	NM_001437539.1		c.2537A>G	p.Asp846Gly	missense	Exon 6 of 6	NP_001424468.1	A0A2R8Y7Z4
TLR5	NM_001437624.1		c.2537A>G	p.Asp846Gly	missense	Exon 4 of 4	NP_001424553.1	A0A2R8Y7Z4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR5	ENST00000642603.2	MANE Select	c.2537A>G	p.Asp846Gly	missense	Exon 6 of 6	ENSP00000496355.1	A0A2R8Y7Z4
TLR5	ENST00000407096.7	TSL:3	c.2537A>G	p.Asp846Gly	missense	Exon 4 of 4	ENSP00000385458.3	B1AZ06
TLR5	ENST00000484766.2	TSL:3	c.2537A>G	p.Asp846Gly	missense	Exon 7 of 7	ENSP00000519510.1	O60602

Frequencies

GnomAD3 genomes

AF:

0.00756

AC:

1150

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00962

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00927

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00704

AC:

1769

AN:

251144

AF XY:

0.00701

show subpopulations

Gnomad AFR exome

AF:

0.00535

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:

0.00930

Gnomad OTH exome

AF:

0.00882

GnomAD4 exome

AF:

0.00884

AC:

12922

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00867

AC XY:

6303

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00720

AC:

241

AN:

33474

American (AMR)

AF:

0.00577

AC:

258

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

428

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00248

AC:

214

AN:

86242

European-Finnish (FIN)

AF:

0.00601

AC:

321

AN:

53414

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00972

AC:

10811

AN:

1111986

Other (OTH)

AF:

0.00939

AC:

567

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

705

1409

2114

2818

3523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

416

832

1248

1664

2080

<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:

0.00760

AC:

1157

AN:

152328

Hom.:

Cov.:

AF XY:

0.00792

AC XY:

590

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00573

AC:

238

AN:

41570

American (AMR)

AF:

0.00961

AC:

147

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00926

AC:

630

AN:

68028

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00909

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:

0.00670

AC:

813

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.7

(source)

DANN

Benign

0.94

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

PhyloP100

-0.11

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

REVEL

Benign

0.031

Sift

Benign

0.19

Sift4G

Benign

0.37

Vest4

0.072

MVP

0.46

MPC

0.068

ClinPred

0.0051

GERP RS

-0.99

gMVP

0.43

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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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