chr4-38828194-A-G

Position:

• chr4-38828194-A-G

Variant summary

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

The ENST00000508254.6(TLR6):​c.1280T>C​(p.Val427Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,986 control chromosomes in the GnomAD database, including 464 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.

• Frequency:
  • Genomes: 𝑓 0.016 (52 hom., cov: 32)
  • Exomes 𝑓: 0.019 (412 hom.)
• Consequence: TLR6 ENST00000508254.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470

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=0.001921922).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR6	NM_006068.5	c.1280T>C	p.Val427Ala	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.1280T>C	p.Val427Ala	missense_variant	2/2	1	NM_006068.5	ENSP00000424718	P1
TLR6	ENST00000381950.2	c.1280T>C	p.Val427Ala	missense_variant	3/3			ENSP00000371376	P1
TLR1	ENST00000506146.5	c.-352-23001T>C		intron_variant		4		ENSP00000423725

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2401 AN: 152164 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0205 AC: 5149 AN: 251222 Hom.: 140 AF XY: 0.0183 AC XY: 2489 AN XY: 135804

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.0785

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00739

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0191 AC: 27877 AN: 1461704 Hom.: 412 Cov.: 37 AF XY: 0.0184 AC XY: 13362 AN XY: 727120

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.0768

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00708

Gnomad4 FIN exome AF: 0.00702

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0158 AC: 2401 AN: 152282 Hom.: 52 Cov.: 32 AF XY: 0.0158 AC XY: 1174 AN XY: 74468

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.0593

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0147 Hom.: 45

Bravo AF: 0.0190

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0179 AC: 2177

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.010
DANN	Benign	0.68
DEOGEN2	Benign	0.045	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.26	T;.
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.13	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.076
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.012
MPC		0.18
ClinPred		0.0065	T
GERP RS		-6.2
Varity_R		0.017
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

Other links and lift over

dbSNP: rs5743815; hg19: chr4-38829815; COSMIC: COSV99062283; COSMIC: COSV99062283;