4-38827350-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006068.5(TLR6):c.2124G>C(p.Gln708His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.25

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017328054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR6	NM_006068.5	c.2124G>C	p.Gln708His	missense_variant	2/2	ENST00000508254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR6	ENST00000508254.6	c.2124G>C	p.Gln708His	missense_variant	2/2	1	NM_006068.5	P1
TLR6	ENST00000381950.2	c.2124G>C	p.Gln708His	missense_variant	3/3			P1
TLR1	ENST00000506146.5	c.-352-22157G>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251488 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135920

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67 AN XY: 727248

Gnomad4 AFR exome AF: 0.00349

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74420

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.00105

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Human Evolutionary Genetics, Institut Pasteur

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.24
MutPred		0.46		Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);.;
MVP		0.51
MPC		0.25
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.90
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137853183; hg19: chr4-38828971;