chr4-38829115-A-G

Variant names:

• chr4-38829115-A-G
• rs5743808
• NM_006068.5:c.359T>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.359T>C​(p.Ile120Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,110 control chromosomes in the GnomAD database, including 649 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. I120V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (234 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (415 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 30 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=0.0017317533).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.087 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR6	NM_006068.5	c.359T>C	p.Ile120Thr	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.359T>C	p.Ile120Thr	missense_variant	Exon 2 of 2	1	NM_006068.5	ENSP00000424718.2
TLR6	ENST00000381950.2	c.359T>C	p.Ile120Thr	missense_variant	Exon 3 of 3	6		ENSP00000371376.1
TLR1	ENST00000506146.5	c.-352-23922T>C		intron_variant	Intron 1 of 5	4		ENSP00000423725.1

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4905 AN: 152196 Hom.: 228 Cov.: 33

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.0762

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0192 AC: 4820 AN: 251300 AF XY: 0.0186

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.0775

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.00894 AC: 13075 AN: 1461796 Hom.: 415 Cov.: 33 AF XY: 0.00966 AC XY: 7027 AN XY: 727184

African (AFR) AF: 0.0903 AC: 3024 AN: 33480

American (AMR) AF: 0.00657 AC: 294 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 147 AN: 26132

East Asian (EAS) AF: 0.0648 AC: 2572 AN: 39684

South Asian (SAS) AF: 0.0400 AC: 3446 AN: 86248

European-Finnish (FIN) AF: 0.00309 AC: 165 AN: 53412

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.00191 AC: 2121 AN: 1111962

Other (OTH) AF: 0.0200 AC: 1208 AN: 60392

GnomAD4 genome AF: 0.0324 AC: 4939 AN: 152314 Hom.: 234 Cov.: 33 AF XY: 0.0324 AC XY: 2414 AN XY: 74474

African (AFR) AF: 0.0894 AC: 3715 AN: 41560

American (AMR) AF: 0.0189 AC: 289 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.0763 AC: 396 AN: 5188

South Asian (SAS) AF: 0.0458 AC: 221 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 68028

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0146 Hom.: 304

Bravo AF: 0.0340

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0808 AC: 356

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.0209 AC: 2535

Asia WGS AF: 0.104 AC: 362 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00332

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.031	T;T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.43	T;.;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	N;N;N;.
PhyloP100		2.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.49	T;T;.;T
Sift4G	Benign	0.42	T;T;T;.
Polyphen		0.0	B;B;.;.
Vest4		0.041
MPC		0.19
ClinPred		0.014	T
GERP RS		2.9
PromoterAI		0.012	Neutral
Varity_R		0.053
gMVP		0.31
Mutation Taster		=99/1	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: rs5743808; hg19: chr4-38830736; COSMIC: COSV67935796; COSMIC: COSV67935796;