1-223111257-T-C

Variant names:

• chr1-223111257-T-C
• rs2072493
• NM_003268.6:c.1775A>G

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.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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars).

• 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
• Publications: 71 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]

TLR5 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus, susceptibility to, 1

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ENSG00000299361 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003268.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR5	NM_003268.6	MANE Select	c.1775A>G	p.Asn592Ser	missense	Exon 6 of 6	NP_003259.2
	TLR5	NM_001437539.1		c.1775A>G	p.Asn592Ser	missense	Exon 6 of 6	NP_001424468.1	A0A2R8Y7Z4
	TLR5	NM_001437624.1		c.1775A>G	p.Asn592Ser	missense	Exon 4 of 4	NP_001424553.1	A0A2R8Y7Z4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR5	ENST00000642603.2	MANE Select	c.1775A>G	p.Asn592Ser	missense	Exon 6 of 6	ENSP00000496355.1	A0A2R8Y7Z4
	TLR5	ENST00000407096.7	TSL:3	c.1775A>G	p.Asn592Ser	missense	Exon 4 of 4	ENSP00000385458.3	B1AZ06
	TLR5	ENST00000484766.2	TSL:3	c.1775A>G	p.Asn592Ser	missense	Exon 7 of 7	ENSP00000519510.1	O60602

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

GnomAD2 exomes AF: 0.155 AC: 39021 AN: 251004 AF XY: 0.154

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 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

African (AFR) AF: 0.0245 AC: 819 AN: 33480

American (AMR) AF: 0.223 AC: 9976 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4160 AN: 26136

East Asian (EAS) AF: 0.310 AC: 12302 AN: 39694

South Asian (SAS) AF: 0.126 AC: 10848 AN: 86254

European-Finnish (FIN) AF: 0.144 AC: 7665 AN: 53410

Middle Eastern (MID) AF: 0.106 AC: 612 AN: 5768

European-Non Finnish (NFE) AF: 0.153 AC: 169843 AN: 1111968

Other (OTH) AF: 0.155 AC: 9353 AN: 60392

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

African (AFR) AF: 0.0305 AC: 1266 AN: 41528

American (AMR) AF: 0.191 AC: 2921 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3466

East Asian (EAS) AF: 0.268 AC: 1386 AN: 5170

South Asian (SAS) AF: 0.133 AC: 639 AN: 4818

European-Finnish (FIN) AF: 0.145 AC: 1538 AN: 10596

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10120 AN: 67998

Other (OTH) AF: 0.130 AC: 275 AN: 2116

Alfa AF: 0.140 Hom.: 4802

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

ClinVar submissions

Significance: Benign; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TLR5-related disorder (1)
-	-	-	Legionnaire disease, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.9
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.043
Sift	Benign	0.73	T
Sift4G	Benign	0.66	T
Vest4		0.031
MPC		0.046
ClinPred		0.0073	T
GERP RS		-10
gMVP		0.17
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: rs2072493; hg19: chr1-223284599; COSMIC: COSV60558244; COSMIC: COSV60558244;