rs5744174

chr1-223111186-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003268.6(TLR5):c.1846T>C(p.Phe616Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,613,888 control chromosomes in the GnomAD database, including 138,857 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (10047 hom., cov: 32)
  • Exomes 𝑓: 0.41 (128810 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.844

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2264728E-4).
• BP6: Variant 1-223111186-A-G is Benign according to our data. Variant chr1-223111186-A-G is described in ClinVar as [Benign]. Clinvar id is 3059715.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-223111186-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR5	NM_003268.6	c.1846T>C	p.Phe616Leu	missense_variant	6/6	ENST00000642603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR5	ENST00000642603.2	c.1846T>C	p.Phe616Leu	missense_variant	6/6		NM_003268.6	P1
TLR5	ENST00000540964.5	c.1846T>C	p.Phe616Leu	missense_variant	4/4	5		P1
TLR5	ENST00000645434.1	c.1846T>C	p.Phe616Leu	missense_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51730 AN: 152034 Hom.: 10044 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.339

GnomAD3 exomes AF: 0.385 AC: 96704 AN: 251150 Hom.: 19955 AF XY: 0.396 AC XY: 53723 AN XY: 135730

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.387

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.413 AC: 604285 AN: 1461736 Hom.: 128810 Cov.: 61 AF XY: 0.415 AC XY: 302083 AN XY: 727160

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.308

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.434

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.392

GnomAD4 genome AF: 0.340 AC: 51760 AN: 152152 Hom.: 10047 Cov.: 32 AF XY: 0.343 AC XY: 25513 AN XY: 74364

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.209

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.339

Alfa AF: 0.405 Hom.: 27166

Bravo AF: 0.315

TwinsUK AF: 0.417 AC: 1545

ALSPAC AF: 0.422 AC: 1627

ESP6500AA AF: 0.168 AC: 742

ESP6500EA AF: 0.420 AC: 3610

ExAC AF: 0.390 AC: 47334

Asia WGS AF: 0.303 AC: 1053 AN: 3478

EpiCase AF: 0.418

EpiControl AF: 0.420

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TLR5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.0060
Dann	Benign	0.19
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.41	T;.;.;T
MetaRNN	Benign	0.00012	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.050	N;.;N;.
REVEL	Benign	0.10
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Vest4		0.0040
MutPred		0.42		Loss of glycosylation at S617 (P = 0.0793);Loss of glycosylation at S617 (P = 0.0793);Loss of glycosylation at S617 (P = 0.0793);Loss of glycosylation at S617 (P = 0.0793);
MPC		0.060
ClinPred		0.017	T
GERP RS		-11
gMVP		0.58

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: rs5744174; hg19: chr1-223284528; COSMIC: COSV60559276; COSMIC: COSV60559276;