rs45528236

Variant names:

• chr1-223112491-G-T
• rs45528236
• NM_003268.6:c.541C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003268.6(TLR5):​c.541C>A​(p.Gln181Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,614,164 control chromosomes in the GnomAD database, including 3,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.044 (189 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3069 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 25 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051743984).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.541C>A	p.Gln181Lys	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.541C>A	p.Gln181Lys	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1

Frequencies

GnomAD3 genomes AF: 0.0442 AC: 6729 AN: 152176 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.0420

GnomAD2 exomes AF: 0.0530 AC: 13317 AN: 251346 AF XY: 0.0570

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.0282

Gnomad FIN exome AF: 0.0465

Gnomad NFE exome AF: 0.0618

Gnomad OTH exome AF: 0.0491

GnomAD4 exome AF: 0.0607 AC: 88671 AN: 1461870 Hom.: 3069 Cov.: 36 AF XY: 0.0619 AC XY: 44995 AN XY: 727238

African (AFR) AF: 0.0217 AC: 726 AN: 33480

American (AMR) AF: 0.0200 AC: 895 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 751 AN: 26136

East Asian (EAS) AF: 0.0178 AC: 707 AN: 39698

South Asian (SAS) AF: 0.101 AC: 8683 AN: 86256

European-Finnish (FIN) AF: 0.0515 AC: 2753 AN: 53416

Middle Eastern (MID) AF: 0.0572 AC: 330 AN: 5768

European-Non Finnish (NFE) AF: 0.0634 AC: 70533 AN: 1111996

Other (OTH) AF: 0.0545 AC: 3293 AN: 60396

GnomAD4 genome AF: 0.0442 AC: 6725 AN: 152294 Hom.: 189 Cov.: 33 AF XY: 0.0444 AC XY: 3309 AN XY: 74466

African (AFR) AF: 0.0237 AC: 984 AN: 41564

American (AMR) AF: 0.0303 AC: 464 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.0274 AC: 142 AN: 5184

South Asian (SAS) AF: 0.102 AC: 491 AN: 4822

European-Finnish (FIN) AF: 0.0441 AC: 468 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0580 AC: 3943 AN: 68022

Other (OTH) AF: 0.0430 AC: 91 AN: 2116

Alfa AF: 0.0541 Hom.: 809

Bravo AF: 0.0400

TwinsUK AF: 0.0588 AC: 218

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.0544 AC: 468

ExAC AF: 0.0556 AC: 6744

Asia WGS AF: 0.0900 AC: 313 AN: 3478

EpiCase AF: 0.0575

EpiControl AF: 0.0559

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.024
DANN	Benign	0.37
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.47	T;.;.;T
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.24
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.080	N;.;N;.
REVEL	Benign	0.051
Sift	Benign	0.82	T;.;T;.
Sift4G	Benign	0.45	T;.;T;.
Vest4		0.020
MPC		0.065
ClinPred		0.000021	T
GERP RS		2.0
gMVP		0.23
Mutation Taster		=90/10	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: rs45528236; hg19: chr1-223285833; COSMIC: COSV60560619; COSMIC: COSV60560619;