4-38828081-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006068.5(TLR6):c.1393G>A(p.Val465Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,613,944 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (160 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (146 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.405

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012029707).
• BP6: Variant 4-38828081-C-T is Benign according to our data. Variant chr4-38828081-C-T is described in ClinVar as [Benign]. Clinvar id is 791975.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR6	NM_006068.5	c.1393G>A	p.Val465Ile	missense_variant	2/2	ENST00000508254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR6	ENST00000508254.6	c.1393G>A	p.Val465Ile	missense_variant	2/2	1	NM_006068.5	P1
TLR6	ENST00000381950.2	c.1393G>A	p.Val465Ile	missense_variant	3/3			P1
TLR1	ENST00000506146.5	c.-352-22888G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3554 AN: 152160 Hom.: 156 Cov.: 33

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00830 AC: 2087 AN: 251366 Hom.: 64 AF XY: 0.00735 AC XY: 999 AN XY: 135884

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00571

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00383 AC: 5597 AN: 1461666 Hom.: 146 Cov.: 37 AF XY: 0.00395 AC XY: 2870 AN XY: 727158

Gnomad4 AFR exome AF: 0.0788

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00501

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000571

Gnomad4 OTH exome AF: 0.00795

GnomAD4 genome AF: 0.0235 AC: 3574 AN: 152278 Hom.: 160 Cov.: 33 AF XY: 0.0239 AC XY: 1777 AN XY: 74468

Gnomad4 AFR AF: 0.0772

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0979 Hom.: 3222

Bravo AF: 0.0257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00995 AC: 1208

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	8.1
Dann	Benign	0.69
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.55	T;.
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.27	N;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;T
Sift4G	Benign	0.97	T;T
Polyphen		0.0	B;B
Vest4		0.064
MVP		0.20
MPC		0.12
ClinPred		0.00040	T
GERP RS		2.6
Varity_R		0.012
gMVP		0.051

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: rs5743816; hg19: chr4-38829702; COSMIC: COSV67935190; COSMIC: COSV67935190;