1-223110872-A-T

Variant names:

• chr1-223110872-A-T
• rs142143294
• NM_003268.6:c.2160T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003268.6(TLR5):​c.2160T>A​(p.Ser720Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,614,248 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.647
• 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]

ENSG00000299361 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0087302625).
• BP6: Variant 1-223110872-A-T is Benign according to our data. Variant chr1-223110872-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3034673.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.2160T>A	p.Ser720Arg	missense_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.2160T>A	p.Ser720Arg	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152250 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00139 AC: 350 AN: 251286 AF XY: 0.00154

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00320 AC: 4680 AN: 1461880 Hom.: 14 Cov.: 33 AF XY: 0.00310 AC XY: 2256 AN XY: 727236

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00411 AC: 4571 AN: 1112010

Other (OTH) AF: 0.00121 AC: 73 AN: 60396

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152368 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74514

African (AFR) AF: 0.000553 AC: 23 AN: 41594

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00317 AC: 216 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00256 Hom.: 1

Bravo AF: 0.00137

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TLR5-related disorder Benign:1

Jan 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.8
DANN	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.75	T;.;.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0087	T;T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		0.65
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D;.;D;.
REVEL	Benign	0.10
Sift	Benign	0.098	T;.;T;.
Sift4G	Benign	0.16	T;.;T;.
Vest4		0.18
MutPred		0.45		Gain of solvent accessibility (P = 0.0739);Gain of solvent accessibility (P = 0.0739);Gain of solvent accessibility (P = 0.0739);Gain of solvent accessibility (P = 0.0739);
MVP		0.64
MPC		0.32
ClinPred		0.041	T
GERP RS		2.4
gMVP		0.36
Mutation Taster		=100/0	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: rs142143294; hg19: chr1-223284214; COSMIC: COSV99046156; COSMIC: COSV99046156;