4-38828729-A-G

Variant names:

• chr4-38828729-A-G
• rs5743810
• NM_006068.5:c.745T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006068.5(TLR6):​c.745T>C​(p.Ser249Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,613,632 control chromosomes in the GnomAD database, including 334,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S249A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (42057 hom., cov: 32)
  • Exomes 𝑓: 0.62 (292592 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.928
• Publications: 222 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1693044E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006068.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR6	NM_006068.5	MANE Select	c.745T>C	p.Ser249Pro	missense	Exon 2 of 2	NP_006059.2
	TLR6	NM_001394553.1		c.745T>C	p.Ser249Pro	missense	Exon 2 of 2	NP_001381482.1	Q9Y2C9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR6	ENST00000508254.6	TSL:1 MANE Select	c.745T>C	p.Ser249Pro	missense	Exon 2 of 2	ENSP00000424718.2	Q9Y2C9-1
	TLR6	ENST00000381950.2	TSL:6	c.745T>C	p.Ser249Pro	missense	Exon 3 of 3	ENSP00000371376.1	Q9Y2C9-1
	TLR6	ENST00000966018.1		c.745T>C	p.Ser249Pro	missense	Exon 2 of 2	ENSP00000636077.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109767 AN: 152042 Hom.: 41993 Cov.: 32

Gnomad AFR AF: 0.926

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.973

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.760

GnomAD2 exomes AF: 0.729 AC: 183018 AN: 250972 AF XY: 0.731

Gnomad AFR exome AF: 0.934

Gnomad AMR exome AF: 0.855

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.615 AC: 899232 AN: 1461472 Hom.: 292592 Cov.: 49 AF XY: 0.626 AC XY: 455335 AN XY: 727014

African (AFR) AF: 0.937 AC: 31367 AN: 33474

American (AMR) AF: 0.848 AC: 37934 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18429 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39668 AN: 39682

South Asian (SAS) AF: 0.971 AC: 83694 AN: 86220

European-Finnish (FIN) AF: 0.519 AC: 27714 AN: 53388

Middle Eastern (MID) AF: 0.849 AC: 4894 AN: 5766

European-Non Finnish (NFE) AF: 0.554 AC: 615479 AN: 1111722

Other (OTH) AF: 0.663 AC: 40053 AN: 60382

GnomAD4 genome AF: 0.722 AC: 109891 AN: 152160 Hom.: 42057 Cov.: 32 AF XY: 0.726 AC XY: 54033 AN XY: 74380

African (AFR) AF: 0.926 AC: 38479 AN: 41540

American (AMR) AF: 0.783 AC: 11979 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2435 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5186

South Asian (SAS) AF: 0.973 AC: 4698 AN: 4830

European-Finnish (FIN) AF: 0.516 AC: 5456 AN: 10566

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.578 AC: 39306 AN: 67968

Other (OTH) AF: 0.763 AC: 1609 AN: 2110

Alfa AF: 0.640 Hom.: 73284

Bravo AF: 0.748

TwinsUK AF: 0.556 AC: 2060

ALSPAC AF: 0.570 AC: 2195

ESP6500AA AF: 0.916 AC: 4036

ESP6500EA AF: 0.577 AC: 4958

ExAC AF: 0.739 AC: 89680

Asia WGS AF: 0.969 AC: 3370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.5
DANN	Benign	0.62
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.93
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.039
Sift	Benign	0.45	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.070
MPC		0.19
ClinPred		0.0015	T
GERP RS		3.5
Varity_R		0.029
gMVP		0.49
Mutation Taster		=100/0	polymorphism (auto)

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: rs5743810; hg19: chr4-38830350; COSMIC: COSV67935256; COSMIC: COSV67935256;