chr1-223111102-T-A

Position:

• chr1-223111102-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003268.6(TLR5):​c.1930A>T​(p.Ile644Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00873 in 1,614,104 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0076 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (76 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.82

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004293859).
• BP6: Variant 1-223111102-T-A is Benign according to our data. Variant chr1-223111102-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 252618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-223111102-T-A is described in Lovd as [Benign].
• 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.1930A>T	p.Ile644Phe	missense_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.1930A>T	p.Ile644Phe	missense_variant	6/6		NM_003268.6	ENSP00000496355	P1
TLR5	ENST00000540964.5	c.1930A>T	p.Ile644Phe	missense_variant	4/4	5		ENSP00000440643	P1
TLR5	ENST00000645434.1	c.1930A>T	p.Ile644Phe	missense_variant	5/5			ENSP00000493892

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1153 AN: 152108 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00520

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00929

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00702 AC: 1764 AN: 251166 Hom.: 11 AF XY: 0.00700 AC XY: 950 AN XY: 135760

Gnomad AFR exome AF: 0.00537

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00884 AC: 12927 AN: 1461878 Hom.: 76 Cov.: 33 AF XY: 0.00867 AC XY: 6307 AN XY: 727242

Gnomad4 AFR exome AF: 0.00717

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.00601

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.00940

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152226 Hom.: 5 Cov.: 32 AF XY: 0.00794 AC XY: 591 AN XY: 74422

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.00968

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00520

Gnomad4 NFE AF: 0.00928

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0100 Hom.: 4

Bravo AF: 0.00795

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00668 AC: 811

Asia WGS AF: 0.00346 AC: 12 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:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TLR5: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.044
DANN	Benign	0.95
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.61	T;.;.;T
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	N;.;N;.
REVEL	Benign	0.057
Sift	Uncertain	0.0080	D;.;D;.
Sift4G	Uncertain	0.0060	D;.;D;.
Vest4		0.23
MVP		0.41
MPC		0.17
ClinPred		0.038	T
GERP RS		-3.5
gMVP		0.48

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: rs5744175; hg19: chr1-223284444;