1-223111186-A-G

Position:

• chr1-223111186-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
TLR5	NM_003268.6	c.1846T>C	p.Phe616Leu	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.1846T>C	p.Phe616Leu	missense_variant	6/6		NM_003268.6	ENSP00000496355	P1
TLR5	ENST00000540964.5	c.1846T>C	p.Phe616Leu	missense_variant	4/4	5		ENSP00000440643	P1
TLR5	ENST00000645434.1	c.1846T>C	p.Phe616Leu	missense_variant	5/5			ENSP00000493892

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: no assertion criteria provided

Submissions by phenotype

TLR5-related disorder Benign:1

Benign, no assertion criteria provided

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;