rs764535

Positions:

• chr1-223112787-G-A
• chr1-223112787-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003268.6(TLR5):​c.245C>T​(p.Thr82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,613,126 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (58 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050294697).
• BP6: Variant 1-223112787-G-A is Benign according to our data. Variant chr1-223112787-G-A is described in ClinVar as [Benign]. Clinvar id is 791521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR5	NM_003268.6	c.245C>T	p.Thr82Ile	missense_variant	6/6	ENST00000642603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR5	ENST00000642603.2	c.245C>T	p.Thr82Ile	missense_variant	6/6		NM_003268.6	P1
TLR5	ENST00000540964.5	c.245C>T	p.Thr82Ile	missense_variant	4/4	5		P1
TLR5	ENST00000645434.1	c.245C>T	p.Thr82Ile	missense_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 643 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00632

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00595 AC: 1493 AN: 250876 Hom.: 19 AF XY: 0.00670 AC XY: 908 AN XY: 135570

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.000834

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00649 AC: 9486 AN: 1460856 Hom.: 58 Cov.: 36 AF XY: 0.00686 AC XY: 4982 AN XY: 726632

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00642

Gnomad4 OTH exome AF: 0.00706

GnomAD4 genome AF: 0.00424 AC: 646 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00424 AC XY: 316 AN XY: 74442

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00634

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00700 Hom.: 7

Bravo AF: 0.00406

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00586 AC: 711

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.91
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.66	T;.;.;T
MetaRNN	Benign	0.0050	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.54	N;.;N;.
REVEL	Benign	0.020
Sift	Benign	0.12	T;.;T;.
Sift4G	Benign	0.27	T;.;T;.
Vest4		0.13
MVP		0.48
MPC		0.061
ClinPred		0.0014	T
GERP RS		3.1
gMVP		0.25

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: rs764535; hg19: chr1-223286129; COSMIC: COSV99046159; COSMIC: COSV99046159;