NM_003268.6:c.2119G>T

Variant names:

• chr1-223110913-C-A
• rs200184447
• NM_003268.6:c.2119G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003268.6(TLR5):​c.2119G>T​(p.Val707Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V707M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

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

ENSG00000299361 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR5	NM_003268.6	MANE Select	c.2119G>T	p.Val707Leu	missense	Exon 6 of 6	NP_003259.2
	TLR5	NM_001437539.1		c.2119G>T	p.Val707Leu	missense	Exon 6 of 6	NP_001424468.1	A0A2R8Y7Z4
	TLR5	NM_001437624.1		c.2119G>T	p.Val707Leu	missense	Exon 4 of 4	NP_001424553.1	A0A2R8Y7Z4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR5	ENST00000642603.2	MANE Select	c.2119G>T	p.Val707Leu	missense	Exon 6 of 6	ENSP00000496355.1	A0A2R8Y7Z4
	TLR5	ENST00000407096.7	TSL:3	c.2119G>T	p.Val707Leu	missense	Exon 4 of 4	ENSP00000385458.3	B1AZ06
	TLR5	ENST00000484766.2	TSL:3	c.2119G>T	p.Val707Leu	missense	Exon 7 of 7	ENSP00000519510.1	O60602

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.74	T
PhyloP100		7.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Vest4		0.56
MutPred		0.63		Gain of ubiquitination at K702 (P = 0.1162)
MVP		0.80
MPC		0.34
ClinPred		0.99	D
GERP RS		5.6
gMVP		0.68
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs200184447; hg19: chr1-223284255;