1-223111186-A-G

Variant names:

• chr1-223111186-A-G
• rs5744174
• NM_003268.6:c.1846T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 142 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]

ENSG00000299361 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 3059715.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.1846T>C	p.Phe616Leu	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.1846T>C	p.Phe616Leu	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1

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

GnomAD2 exomes AF: 0.385 AC: 96704 AN: 251150 AF XY: 0.396

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 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

African (AFR) AF: 0.141 AC: 4728 AN: 33478

American (AMR) AF: 0.308 AC: 13788 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 10097 AN: 26136

East Asian (EAS) AF: 0.175 AC: 6937 AN: 39672

South Asian (SAS) AF: 0.434 AC: 37440 AN: 86252

European-Finnish (FIN) AF: 0.501 AC: 26763 AN: 53412

Middle Eastern (MID) AF: 0.363 AC: 2095 AN: 5768

European-Non Finnish (NFE) AF: 0.431 AC: 478771 AN: 1111912

Other (OTH) AF: 0.392 AC: 23666 AN: 60396

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

African (AFR) AF: 0.156 AC: 6483 AN: 41530

American (AMR) AF: 0.325 AC: 4972 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3472

East Asian (EAS) AF: 0.209 AC: 1084 AN: 5178

South Asian (SAS) AF: 0.428 AC: 2060 AN: 4810

European-Finnish (FIN) AF: 0.494 AC: 5219 AN: 10570

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.431 AC: 29269 AN: 67986

Other (OTH) AF: 0.339 AC: 717 AN: 2112

Alfa AF: 0.387 Hom.: 38039

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

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
DEOGEN2	Benign	0.0	.;.;.;.
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
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		-0.84
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
ClinPred		0.017	T
GERP RS		-11
gMVP		0.58
Mutation Taster		=100/0	polymorphism (auto)

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