1-223110627-T-C

Position:

• chr1-223110627-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003268.6(TLR5):​c.2405A>G​(p.Lys802Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08846682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR5	NM_003268.6	c.2405A>G	p.Lys802Arg	missense_variant	6/6	ENST00000642603.2	NP_003259.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR5	ENST00000642603.2	c.2405A>G	p.Lys802Arg	missense_variant	6/6		NM_003268.6	ENSP00000496355	P1
TLR5	ENST00000540964.5	c.2405A>G	p.Lys802Arg	missense_variant	4/4	5		ENSP00000440643	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.2405A>G (p.K802R) alteration is located in exon 6 (coding exon 1) of the TLR5 gene. This alteration results from a A to G substitution at nucleotide position 2405, causing the lysine (K) at amino acid position 802 to be replaced by an arginine (R). 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	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;.;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.49	N;.;N
REVEL	Benign	0.043
Sift	Benign	0.43	T;.;T
Sift4G	Benign	0.30	T;.;T
Vest4		0.097
MutPred		0.51		Gain of MoRF binding (P = 0.0889);Gain of MoRF binding (P = 0.0889);Gain of MoRF binding (P = 0.0889);
MVP		0.38
MPC		0.099
ClinPred		0.19	T
GERP RS		0.67
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-223283969;