4-38828211-T-C

Position:

• chr4-38828211-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000508254.6(TLR6):​c.1263A>G​(p.Lys421=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,613,206 control chromosomes in the GnomAD database, including 106,819 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.44 (16127 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90692 hom.)
• Consequence: TLR6 ENST00000508254.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.978

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP7: Synonymous conserved (PhyloP=-0.978 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR6	NM_006068.5	c.1263A>G	p.Lys421=	synonymous_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.1263A>G	p.Lys421=	synonymous_variant	2/2	1	NM_006068.5	ENSP00000424718	P1
TLR6	ENST00000381950.2	c.1263A>G	p.Lys421=	synonymous_variant	3/3			ENSP00000371376	P1
TLR1	ENST00000506146.5	c.-352-23018A>G		intron_variant		4		ENSP00000423725

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66178 AN: 151930 Hom.: 16096 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.400

GnomAD3 exomes AF: 0.372 AC: 93513 AN: 251194 Hom.: 18429 AF XY: 0.366 AC XY: 49700 AN XY: 135786

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.381

Gnomad SAS exome AF: 0.377

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.347 AC: 506652 AN: 1461158 Hom.: 90692 Cov.: 49 AF XY: 0.347 AC XY: 252305 AN XY: 726760

Gnomad4 AFR exome AF: 0.675

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.436 AC: 66262 AN: 152048 Hom.: 16127 Cov.: 32 AF XY: 0.436 AC XY: 32385 AN XY: 74318

Gnomad4 AFR AF: 0.663

Gnomad4 AMR AF: 0.339

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.369

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.404

Alfa AF: 0.347 Hom.: 12805

Bravo AF: 0.436

Asia WGS AF: 0.440 AC: 1529 AN: 3478

EpiCase AF: 0.336

EpiControl AF: 0.324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.48
DANN	Benign	0.63

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: rs3775073; hg19: chr4-38829832; COSMIC: COSV67935197; COSMIC: COSV67935197;