chr1-223110828-A-G

Variant names:

• chr1-223110828-A-G
• NM_003268.6:c.2204T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003268.6(TLR5):​c.2204T>C​(p.Val735Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TLR5 NM_003268.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40728515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR5	NM_003268.6	c.2204T>C	p.Val735Ala	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.2204T>C	p.Val735Ala	missense_variant	Exon 6 of 6		NM_003268.6	ENSP00000496355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2204T>C (p.V735A) alteration is located in exon 6 (coding exon 1) of the TLR5 gene. This alteration results from a T to C substitution at nucleotide position 2204, causing the valine (V) at amino acid position 735 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;.;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		8.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;.;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;.;D;.
Sift4G	Uncertain	0.017	D;.;D;.
Vest4		0.14
MutPred		0.66		Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);
MVP		0.69
MPC		0.13
ClinPred		0.80	D
GERP RS		5.8
gMVP		0.17
Mutation Taster		=69/31	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

hg19: chr1-223284170;