1-223111257-T-C

Variant names:

• chr1-223111257-T-C
• rs2072493
• NM_003268.6:c.1775A>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.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,risk factor (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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; risk factor no assertion criteria provided 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 -13 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, risk_factor]. Clinvar id is 6659.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.1775A>G	p.Asn592Ser	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.1775A>G	p.Asn592Ser	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1
TLR5	ENST00000540964.5	c.1775A>G	p.Asn592Ser	missense_variant	Exon 4 of 4	5
TLR5	ENST00000645434.1	c.1775A>G	p.Asn592Ser	missense_variant	Exon 5 of 5			ENSP00000493892.2

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; risk factor

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

TLR5-related disorder Benign:1

Nov 21, 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). -

Legionnaire disease, susceptibility to Other:1

Nov 17, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
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;