rs45528236

Positions:

• chr1-223112491-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.044 (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

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=0.0051743984).
• BP6: Variant 1-223112491-G-T is Benign according to our data. Variant chr1-223112491-G-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TLR5	NM_003268.6	c.541C>A	p.Gln181Lys	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.541C>A	p.Gln181Lys	missense_variant	6/6		NM_003268.6	ENSP00000496355	P1
TLR5	ENST00000540964.5	c.541C>A	p.Gln181Lys	missense_variant	4/4	5		ENSP00000440643	P1
TLR5	ENST00000645434.1	c.541C>A	p.Gln181Lys	missense_variant	5/5			ENSP00000493892

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

GnomAD3 exomes AF: 0.0530 AC: 13317 AN: 251346 Hom.: 459 AF XY: 0.0570 AC XY: 7738 AN XY: 135864

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 SAS exome AF: 0.103

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

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.0200

Gnomad4 ASJ exome AF: 0.0287

Gnomad4 EAS exome AF: 0.0178

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0515

Gnomad4 NFE exome AF: 0.0634

Gnomad4 OTH exome AF: 0.0545

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

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.0441

Gnomad4 NFE AF: 0.0580

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0553 Hom.: 403

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
MutationTaster	Benign	1.0	N;N;N
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

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: rs45528236; hg19: chr1-223285833; COSMIC: COSV60560619; COSMIC: COSV60560619;