chr1-223111087-T-G

Variant names:

• chr1-223111087-T-G
• rs760506250
• NM_003268.6:c.1945A>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.1945A>C​(p.Thr649Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.125

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=0.15632868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.1945A>C	p.Thr649Pro	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	c.1945A>C	p.Thr649Pro	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1
TLR5	ENST00000540964.5	c.1945A>C	p.Thr649Pro	missense_variant	Exon 4 of 4	5
TLR5	ENST00000645434.1	c.1945A>C	p.Thr649Pro	missense_variant	Exon 5 of 5			ENSP00000493892.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251134 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1945A>C (p.T649P) alteration is located in exon 6 (coding exon 1) of the TLR5 gene. This alteration results from a A to C substitution at nucleotide position 1945, causing the threonine (T) at amino acid position 649 to be replaced by a proline (P). 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	-0.36	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.97
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.78	T;.;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.1	N;.;N;.
REVEL	Benign	0.20
Sift	Uncertain	0.022	D;.;D;.
Sift4G	Uncertain	0.025	D;.;D;.
Vest4		0.42
MutPred		0.64		Loss of catalytic residue at T649 (P = 0.0412);Loss of catalytic residue at T649 (P = 0.0412);Loss of catalytic residue at T649 (P = 0.0412);Loss of catalytic residue at T649 (P = 0.0412);
MVP		0.59
MPC		0.13
ClinPred		0.077	T
GERP RS		-1.4
gMVP		0.47

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

Other links and lift over

dbSNP: rs760506250; hg19: chr1-223284429;