1-223110539-T-C

Variant names:

• chr1-223110539-T-C
• rs75283814
• NM_003268.6:c.2493A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003268.6(TLR5):​c.2493A>G​(p.Lys831Lys) 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
• Publications: 9 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]

ENSG00000299361 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.2493A>G	p.Lys831Lys	synonymous_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.2493A>G	p.Lys831Lys	synonymous_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1

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

GnomAD2 exomes AF: 0.00671 AC: 1686 AN: 251382 AF XY: 0.00675

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 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

African (AFR) AF: 0.00239 AC: 80 AN: 33478

American (AMR) AF: 0.00539 AC: 241 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 428 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86258

European-Finnish (FIN) AF: 0.00601 AC: 321 AN: 53414

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.00972 AC: 10804 AN: 1112000

Other (OTH) AF: 0.00854 AC: 516 AN: 60396

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

African (AFR) AF: 0.00195 AC: 81 AN: 41508

American (AMR) AF: 0.00805 AC: 123 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 56 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.00519 AC: 55 AN: 10592

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00922 AC: 627 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

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

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TLR5: BP4, BP7, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.5
DANN	Benign	0.63
PhyloP100		0.097
Mutation Taster		=98/2	polymorphism

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: rs75283814; hg19: chr1-223283881; COSMIC: COSV108191429;