4-38828729-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S249A) has been classified as Likely benign.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR6	NM_006068.5	c.745T>C	p.Ser249Pro	missense_variant	Exon 2 of 2	ENST00000508254.6	NP_006059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR6	ENST00000508254.6	c.745T>C	p.Ser249Pro	missense_variant	Exon 2 of 2	1	NM_006068.5	ENSP00000424718.2
TLR6	ENST00000381950.2	c.745T>C	p.Ser249Pro	missense_variant	Exon 3 of 3	6		ENSP00000371376.1
TLR1	ENST00000506146.5	c.-352-23536T>C		intron_variant	Intron 1 of 5	4		ENSP00000423725.1

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

GnomAD3 exomes AF: 0.729 AC: 183018 AN: 250972 Hom.: 70806 AF XY: 0.731 AC XY: 99180 AN XY: 135738

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 SAS exome AF: 0.972

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

Gnomad4 AFR exome AF: 0.937

Gnomad4 AMR exome AF: 0.848

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.971

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.663

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

Gnomad4 AFR AF: 0.926

Gnomad4 AMR AF: 0.783

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.973

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.763

Alfa AF: 0.623 Hom.: 47676

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 v4.3

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;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.15	T;.;T
MetaRNN	Benign	0.0000012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N;N;.
REVEL	Benign	0.039
Sift	Benign	0.45	T;T;.
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.070
MPC		0.19
ClinPred		0.0015	T
GERP RS		3.5
Varity_R		0.029
gMVP		0.49

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; COSMIC: COSV67935256; COSMIC: COSV67935256;