1-223138521-T-C

Variant names:

• chr1-223138521-T-C
• rs2353476
• NM_003268.6:c.-438-1258A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003268.6(TLR5):​c.-438-1258A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 151,846 control chromosomes in the GnomAD database, including 28,383 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (28383 hom., cov: 31)
• Consequence: TLR5 NM_003268.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 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.-438-1258A>G		intron	N/A	NP_003259.2
	TLR5	NM_001437539.1		c.-532-1258A>G		intron	N/A	NP_001424468.1	A0A2R8Y7Z4
	TLR5	NM_001437624.1		c.-352-3657A>G		intron	N/A	NP_001424553.1	A0A2R8Y7Z4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR5	ENST00000642603.2	MANE Select	c.-438-1258A>G		intron	N/A	ENSP00000496355.1	A0A2R8Y7Z4
	TLR5	ENST00000407096.7	TSL:3	c.-352-3657A>G		intron	N/A	ENSP00000385458.3	B1AZ06
	TLR5	ENST00000484766.2	TSL:3	c.-532-1258A>G		intron	N/A	ENSP00000519510.1	O60602

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91228 AN: 151728 Hom.: 28361 Cov.: 31

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.601

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.601 AC: 91295 AN: 151846 Hom.: 28383 Cov.: 31 AF XY: 0.599 AC XY: 44471 AN XY: 74182

African (AFR) AF: 0.742 AC: 30728 AN: 41412

American (AMR) AF: 0.633 AC: 9659 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1965 AN: 3466

East Asian (EAS) AF: 0.760 AC: 3913 AN: 5152

South Asian (SAS) AF: 0.575 AC: 2767 AN: 4810

European-Finnish (FIN) AF: 0.475 AC: 4991 AN: 10512

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35419 AN: 67912

Other (OTH) AF: 0.600 AC: 1265 AN: 2110

Alfa AF: 0.581 Hom.: 9847

Bravo AF: 0.623

Asia WGS AF: 0.684 AC: 2378 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.81
DANN	Benign	0.59
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2353476; hg19: chr1-223311863;