4-38828054-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006068.5(TLR6):​c.1420G>A​(p.Ala474Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,190 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A474V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 120 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 126 hom. )

Consequence

TLR6
NM_006068.5 missense

Scores

18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.496
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.001205653).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0723 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TLR6NM_006068.5 linkuse as main transcriptc.1420G>A p.Ala474Thr missense_variant 2/2 ENST00000508254.6 NP_006059.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TLR6ENST00000508254.6 linkuse as main transcriptc.1420G>A p.Ala474Thr missense_variant 2/21 NM_006068.5 ENSP00000424718 P1Q9Y2C9-1
TLR6ENST00000381950.2 linkuse as main transcriptc.1420G>A p.Ala474Thr missense_variant 3/3 ENSP00000371376 P1Q9Y2C9-1
TLR1ENST00000506146.5 linkuse as main transcriptc.-352-22861G>A intron_variant 4 ENSP00000423725

Frequencies

GnomAD3 genomes
AF:
0.0213
AC:
3248
AN:
152180
Hom.:
120
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0745
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00765
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.0148
GnomAD3 exomes
AF:
0.00559
AC:
1406
AN:
251442
Hom.:
55
AF XY:
0.00413
AC XY:
561
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.0783
Gnomad AMR exome
AF:
0.00306
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00215
AC:
3146
AN:
1461892
Hom.:
126
Cov.:
36
AF XY:
0.00182
AC XY:
1324
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0784
Gnomad4 AMR exome
AF:
0.00351
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.000162
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000405
Gnomad4 OTH exome
AF:
0.00474
GnomAD4 genome
AF:
0.0214
AC:
3257
AN:
152298
Hom.:
120
Cov.:
32
AF XY:
0.0210
AC XY:
1566
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0745
Gnomad4 AMR
AF:
0.00758
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.0147
Alfa
AF:
0.00652
Hom.:
16
Bravo
AF:
0.0247
ESP6500AA
AF:
0.0769
AC:
339
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00712
AC:
864
Asia WGS
AF:
0.00433
AC:
15
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
12
DANN
Benign
0.91
DEOGEN2
Benign
0.062
T;T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.85
D;.
MetaRNN
Benign
0.0012
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.39
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.041
Sift
Benign
0.23
T;T
Sift4G
Benign
0.15
T;T
Polyphen
0.0
B;B
Vest4
0.038
MVP
0.50
MPC
0.15
ClinPred
0.00049
T
GERP RS
0.52
Varity_R
0.051
gMVP
0.16

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5743817; hg19: chr4-38829675; API