chr1-223110539-T-C

Position:

• chr1-223110539-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003268.6(TLR5):​c.2493A>G​(p.Lys831=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 1,614,036 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (69 hom.)
• Consequence: TLR5 NM_003268.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0970

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-223110539-T-C is Benign according to our data. Variant chr1-223110539-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 785793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.097 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR5	NM_003268.6	c.2493A>G	p.Lys831=	synonymous_variant	6/6	ENST00000642603.2	NP_003259.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR5	ENST00000642603.2	c.2493A>G	p.Lys831=	synonymous_variant	6/6		NM_003268.6	ENSP00000496355	P1
TLR5	ENST00000540964.5	c.2493A>G	p.Lys831=	synonymous_variant	4/4	5		ENSP00000440643	P1

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 970 AN: 152048 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00519

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00923

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00671 AC: 1686 AN: 251382 Hom.: 11 AF XY: 0.00675 AC XY: 917 AN XY: 135874

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.00925

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.00866 AC: 12664 AN: 1461870 Hom.: 69 Cov.: 32 AF XY: 0.00851 AC XY: 6190 AN XY: 727234

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00243

Gnomad4 FIN exome AF: 0.00601

Gnomad4 NFE exome AF: 0.00972

Gnomad4 OTH exome AF: 0.00854

GnomAD4 genome AF: 0.00637 AC: 969 AN: 152166 Hom.: 5 Cov.: 32 AF XY: 0.00675 AC XY: 502 AN XY: 74388

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.0162

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00519

Gnomad4 NFE AF: 0.00922

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00903 Hom.: 6

Bravo AF: 0.00650

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TLR5: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.5
DANN	Benign	0.63

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: rs75283814; hg19: chr1-223283881;