1-223111257-T-C

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.1775A>G(p.Asn592Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,613,986 control chromosomes in the GnomAD database, including 20,121 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 0.12 (1461 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18660 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -2.93

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=0.0072398484).
• BP6: Variant 1-223111257-T-C is Benign according to our data. Variant chr1-223111257-T-C is described in ClinVar as [Benign]. Clinvar id is 6659.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR5	NM_003268.6	c.1775A>G	p.Asn592Ser	missense_variant	6/6	ENST00000642603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR5	ENST00000642603.2	c.1775A>G	p.Asn592Ser	missense_variant	6/6		NM_003268.6	P1
TLR5	ENST00000540964.5	c.1775A>G	p.Asn592Ser	missense_variant	4/4	5		P1
TLR5	ENST00000645434.1	c.1775A>G	p.Asn592Ser	missense_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18796 AN: 152066 Hom.: 1459 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.155 AC: 39021 AN: 251004 Hom.: 3358 AF XY: 0.154 AC XY: 20831 AN XY: 135654

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.244

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.154 AC: 225578 AN: 1461802 Hom.: 18660 Cov.: 40 AF XY: 0.153 AC XY: 111274 AN XY: 727184

Gnomad4 AFR exome AF: 0.0245

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.124 AC: 18800 AN: 152184 Hom.: 1461 Cov.: 32 AF XY: 0.126 AC XY: 9393 AN XY: 74398

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.130

Alfa AF: 0.144 Hom.: 3460

Bravo AF: 0.123

TwinsUK AF: 0.169 AC: 627

ALSPAC AF: 0.154 AC: 592

ESP6500AA AF: 0.0327 AC: 144

ESP6500EA AF: 0.160 AC: 1373

ExAC AF: 0.149 AC: 18038

Asia WGS AF: 0.191 AC: 664 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other: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

Nov 21, 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). -

Legionnaire disease, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 17, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.0010
Dann	Benign	0.27
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.095	T;.;.;T
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.17	N;.;N;.
REVEL	Benign	0.043
Sift	Benign	0.73	T;.;T;.
Sift4G	Benign	0.66	T;.;T;.
Vest4		0.031
MPC		0.046
ClinPred		0.0073	T
GERP RS		-10
gMVP		0.17

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: rs2072493; hg19: chr1-223284599; COSMIC: COSV60558244; COSMIC: COSV60558244;