1-223111700-G-A

Variant names:

• chr1-223111700-G-A
• rs5744169
• NM_003268.6:c.1332C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003268.6(TLR5):​c.1332C>T​(p.Leu444Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,614,154 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (82 hom.)
• Consequence: TLR5 NM_003268.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0550
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-223111700-G-A is Benign according to our data. Variant chr1-223111700-G-A is described in ClinVar as Benign. ClinVar VariationId is 775671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.055 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 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.1332C>T	p.Leu444Leu	synonymous	Exon 6 of 6	NP_003259.2
	TLR5	NM_001437539.1		c.1332C>T	p.Leu444Leu	synonymous	Exon 6 of 6	NP_001424468.1	A0A2R8Y7Z4
	TLR5	NM_001437624.1		c.1332C>T	p.Leu444Leu	synonymous	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.1332C>T	p.Leu444Leu	synonymous	Exon 6 of 6	ENSP00000496355.1	A0A2R8Y7Z4
	TLR5	ENST00000407096.7	TSL:3	c.1332C>T	p.Leu444Leu	synonymous	Exon 4 of 4	ENSP00000385458.3	B1AZ06
	TLR5	ENST00000484766.2	TSL:3	c.1332C>T	p.Leu444Leu	synonymous	Exon 7 of 7	ENSP00000519510.1	O60602

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2919 AN: 152170 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00509 AC: 1280 AN: 251252 AF XY: 0.00370

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00199 AC: 2916 AN: 1461866 Hom.: 82 Cov.: 36 AF XY: 0.00175 AC XY: 1274 AN XY: 727232

African (AFR) AF: 0.0663 AC: 2221 AN: 33480

American (AMR) AF: 0.00394 AC: 176 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000196 AC: 218 AN: 1112004

Other (OTH) AF: 0.00440 AC: 266 AN: 60396

GnomAD4 genome AF: 0.0193 AC: 2933 AN: 152288 Hom.: 84 Cov.: 32 AF XY: 0.0186 AC XY: 1388 AN XY: 74472

African (AFR) AF: 0.0670 AC: 2781 AN: 41538

American (AMR) AF: 0.00667 AC: 102 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68030

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00805 Hom.: 34

Bravo AF: 0.0220

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.51
DANN	Benign	0.53
PhyloP100		-0.055
Mutation Taster		=98/2	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: rs5744169; hg19: chr1-223285042;