Variant 1-223111041-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003268.6(TLR5):c.1991G>A(p.Arg664Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TLR5
NM_003268.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR5	NM_003268.6 linkuse as main transcript	c.1991G>A	p.Arg664Gln	missense_variant	6/6	ENST00000642603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TLR5	ENST00000642603.2 linkuse as main transcript	c.1991G>A	p.Arg664Gln	missense_variant	6/6		NM_003268.6	P1
TLR5	ENST00000540964.5 linkuse as main transcript	c.1991G>A	p.Arg664Gln	missense_variant	4/4	5		P1
TLR5	ENST00000645434.1 linkuse as main transcript	c.1991G>A	p.Arg664Gln	missense_variant	5/5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250966

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.1991G>A (p.R664Q) alteration is located in exon 6 (coding exon 1) of the TLR5 gene. This alteration results from a G to A substitution at nucleotide position 1991, causing the arginine (R) at amino acid position 664 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

0.0067

BayesDel_noAF

Uncertain

-0.050

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;.;D

M_CAP

Benign

0.083

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-0.41

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

D;.;D;.

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Vest4

0.68

MutPred

0.60

Loss of methylation at R664 (P = 0.0112);Loss of methylation at R664 (P = 0.0112);Loss of methylation at R664 (P = 0.0112);Loss of methylation at R664 (P = 0.0112);

MVP

0.78

MPC

0.37

ClinPred

0.98

GERP RS

5.5

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over