4-38828495-C-T

Position:

• chr4-38828495-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000508254.6(TLR6):​c.979G>A​(p.Val327Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,614,054 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (169 hom.)
• Consequence: TLR6 ENST00000508254.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219

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=0.002669394).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR6	NM_006068.5	c.979G>A	p.Val327Met	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.979G>A	p.Val327Met	missense_variant	2/2	1	NM_006068.5	ENSP00000424718	P1
TLR6	ENST00000381950.2	c.979G>A	p.Val327Met	missense_variant	3/3			ENSP00000371376	P1
TLR1	ENST00000506146.5	c.-352-23302G>A		intron_variant		4		ENSP00000423725

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2031 AN: 152162 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0121 AC: 3042 AN: 251140 Hom.: 78 AF XY: 0.0122 AC XY: 1659 AN XY: 135822

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.0721

Gnomad SAS exome AF: 0.0216

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.00593 AC: 8671 AN: 1461774 Hom.: 169 Cov.: 36 AF XY: 0.00644 AC XY: 4685 AN XY: 727184

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.0618

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.00309

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0134 AC: 2036 AN: 152280 Hom.: 45 Cov.: 33 AF XY: 0.0135 AC XY: 1003 AN XY: 74462

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.0722

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00687 Hom.: 58

Bravo AF: 0.0134

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.0126 AC: 1531

Asia WGS AF: 0.0680 AC: 238 AN: 3476

EpiCase AF: 0.00251

EpiControl AF: 0.00284

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.7
DANN	Benign	0.96
DEOGEN2	Benign	0.058	T;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.12	T;.;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N;N;.
REVEL	Benign	0.049
Sift	Benign	0.099	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.30	B;B;.
Vest4		0.15
MPC		0.16
ClinPred		0.0068	T
GERP RS		0.62
Varity_R		0.024
gMVP		0.44

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: rs3796508; hg19: chr4-38830116; COSMIC: COSV67935792; COSMIC: COSV67935792;