4-38828729-A-C

Position:

• chr4-38828729-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006068.5(TLR6):​c.745T>G​(p.Ser249Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S249P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 0.928

Genes affected

TLR6 (HGNC:16711): (toll like receptor 6) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor functionally interacts with toll-like receptor 2 to mediate cellular response to bacterial lipoproteins. A Ser249Pro polymorphism in the extracellular domain of the encoded protein may be associated with an increased of asthma is some populations.[provided by RefSeq, Jan 2011]

TLR1 (HGNC:11847): (toll like receptor 1) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04555121).
• BP6: Variant 4-38828729-A-C is Benign according to our data. Variant chr4-38828729-A-C is described in ClinVar as [protective]. Clinvar id is 1710535.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_benign, oryginal submission is: [protective].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR6	NM_006068.5	c.745T>G	p.Ser249Ala	missense_variant	2/2	ENST00000508254.6	NP_006059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR6	ENST00000508254.6	c.745T>G	p.Ser249Ala	missense_variant	2/2	1	NM_006068.5	ENSP00000424718	P1
TLR6	ENST00000381950.2	c.745T>G	p.Ser249Ala	missense_variant	3/3			ENSP00000371376	P1
TLR1	ENST00000506146.5	c.-352-23536T>G		intron_variant		4		ENSP00000423725

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Leprosy, susceptibility to, 1 Benign:1

protective, no assertion criteria provided

case-control

Centro Dermatológico Federico Lleras Acosta, Hospital Universitario Centro Dermatológico Federico Lleras Acosta

Jun 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.2
DANN	Benign	0.60
DEOGEN2	Benign	0.080	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	T;.;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.49	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N;N;.
REVEL	Benign	0.062
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.097
MutPred		0.49		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP		0.26
MPC		0.13
ClinPred		0.023	T
GERP RS		3.5
Varity_R		0.021
gMVP		0.19

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: rs5743810; hg19: chr4-38830350;